Macrocyclic picolinamides as fungicides

ABSTRACT

The disclosure relates to macrocyclic picolinamides of Formula (I) and to the use of these compounds as fungicides.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 61/747,723 filed Dec. 31, 2012, which is expresslyincorporated by reference herein.

BACKGROUND AND SUMMARY

Fungicides are compounds, of natural or synthetic origin, which act toprotect and/or cure plants against damage caused by agriculturallyrelevant fungi. Generally, no single fungicide is useful in allsituations. Consequently, research is ongoing to produce fungicides thatmay have better performance, are easier to use, and cost less.

The present disclosure relates to macrocyclic picolinamides and theiruse as fungicides. The compounds of the present disclosure may offerprotection against ascomycetes, basidiomycetes, deuteromycetes andoomycetes.

One embodiment of the present disclosure may include compounds ofFormula I:

-   -   X is H or C(O)R₅;    -   Y is H, C(O)R₅, or Q;    -   Q is

-   -   R₁ is H, alkyl, alkenyl, aryl, —C(O)R₄, each substituted with 0,        1 or multiple R₄;    -   R₂ is H, alkyl, alkenyl, aryl, —C(O)R₄, each substituted with 0,        1 or multiple R₄;    -   R₃ is H, —C(O)R₆ or —CH₂OC(O)R₆;    -   R₄ is alkyl, alkenyl, halo, haloalkyl, alkoxy, or aryl;    -   R₅ is alkyl, alkoxy, benzyl, benzyloxy, each substituted with 0,        1, or multiple R₇, wherein each R₇ may be substituted with 0, 1,        or multiple R₄;    -   R₆ is alkyl or alkoxy, each substituted with 0, 1, or multiple        R⁴;    -   R₇ is alkyl, alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl,        carbocyclic, heterocyclic,—Si(R₄)₃, —C(O)R₄, —S(O)_(n)R₄, each        substituted with 0, 1, or multiple R₄;    -   and with the proviso that when R₁ and R₂ are H then X and Y are        C(O)R₅ and R₅ is tert-butoxy.

Another embodiment of the present disclosure may include a fungicidalcomposition for the control or prevention of fungal attack comprisingthe compounds described above and a phytologically acceptable carriermaterial.

Yet another embodiment of the present disclosure may include a methodfor the control or prevention of fungal attack on a plant, the methodincluding the steps of applying a fungicidally effective amount of oneor more of the compounds described above to at least one of the fungus,the plant, an area adjacent to the plant, and the seed adapted toproduce the plant.

The term “alkyl” refers to a branched or unbranched carbon chain,including methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tertiarybutyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyland the like.

The term “alkenyl” refers to a branched or unbranched carbon chaincontaining one or more double bonds including ethenyl, propenyl,butenyl, isopropenyl, isobutenyl, cyclopentenyl, cyclohexenyl, and thelike.

The term “alkynyl” refers to a branched or unbranched carbon chaincontaining one or more triple bonds including propynyl, butynyl and thelike.

The term “aryl” refers to any aromatic, mono- or bi-cyclic, containing 0heteroatoms.

The term “heterocyclyl” refers to any aromatic or non-aromatic ring,mono- or bi-cyclic, containing one or more heteroatoms

The term “cycloalkyl” refers to any monocyclic or polycyclic, saturatedsubstituent consisting of carbon and hydrogen, for example, cyclopropyl,cyclobutyl, cyclopentyl, norbornyl, bicyclo[2.2.2]octyl, anddecahydronaphthyl.

The term “cycloalkenyl” refers to any monocyclic or polycyclic,unsaturated (at least one carbon-carbon double bond) substituentconsisting of carbon and hydrogen, for example, cyclobutenyl,cyclopentenyl, cyclohexenyl, norbornenyl, bicyclo[2.2.2]octenyl,tetrahydronaphthyl, hexahydronaphthyl, and octahydronaphthyl.

The term “alkoxy” refers to an —OR substituent.

The term “alkoxycarbonyl” refers to a —C(O)—OR substituent.

The term “alkylcarbonyl” refers to a —C(O)—R substituent.

The term “alkylsulfonyl” refers to an —SO₂—R substituent.

The term “haloalkylsulfonyl” refers to an —SO₂—R substituent where R isfully or partially substituted with Cl, F, I, or Br or any combinationthereof.

The term “alkylthio” refers to an —S—R substituent.

The term “haloalkylthio” refers to an alkylthio, which is substitutedwith Cl, F, I, or Br or any combination thereof.

The term “alkylaminocarbonyl” refers to a —C(O)-N(H)-R substituent.

The term “dialkylaminocarbonyl” refers to a —C(O)-NR₂ substituent.

The term “alkylcycloalkylamino” refers to a cycloalkylamino substituentthat is substituted with an alkyl group.

The term “trialkylsilyl” refers to —SiR₃.

The term “cyano” refers to a —C═N substituent.

The term “hydroxyl” refers to an —OH substituent.

The term “amino” refers to a —NH₂ substituent.

The term “alkylamino” refers to a —N(H)—R substituent.

The term “dialkylamino” refers to a —NR₂ substituent.

The term “alkoxyalkoxy” refers to —O(CH₂)_(n)O(CH₂)_(n) where n is aninteger selected from the list 1, 2, 3, 4, 5, or 6.

The term “alkoxyalkyl” refers to an alkoxy substitution on an alkyl.

The term “haloalkoxyalkyl” refers to an alkoxy substitution on an alkylwhich may be partially substituted with halogen atoms.

The term “hydroxyalkyl” refers to an alkyl which is substituted with ahydroxyl group.

The term “haloalkoxy” refers to an —OR-X substituent, wherein X is Cl,F, Br, or I, or any combination thereof.

The term “haloalkyl” refers to an alkyl, which is substituted with Cl,F, I, or Br or any combination thereof.

The term “haloalkenyl” refers to an alkenyl, which is substituted withCl, F, I, or Br or any combination thereof.

The term “haloalkynyl” refers to an alkynyl which is substituted withCl, F, I, or Br or any combination thereof.

The term “halogen” or “halo” refers to one or more halogen atoms,defined as F, Cl, Br, and I.

The term “hydroxycarbonyl” refers to a —C(O)—OH sub stituent.

The term “nitro” refers to a —NO₂ substituent.

The term “optionally substituted with” a substituent means containing 0,1, or more of that substituent.

Unless specifically noted or clearly implied otherwise the term “about”refers to a range of values of plus or minus 10 percent, e.g. about 1refers to the range 0.9 to 1.1.

Throughout the disclosure, reference to the compounds of Formula I isread as also including diastereomers, enantiomers, and mixtures thereofIn another embodiment, Formula (I) is read as also including salts orhydrates thereof. Exemplary salts include, but are not limited to:hydrochloride, hydrobromide, and hydroiodide.

It is also understood by those skilled in the art that additionalsubstitution is allowable, unless otherwise noted, as long as the rulesof chemical bonding and strain energy are satisfied and the productstill exhibits fungicidal activity.

Another embodiment of the present disclosure is a use of a compound ofFormula I, for protection of a plant against attack by a phytopathogenicorganism or the treatment of a plant infested by a phytopathogenicorganism, comprising the application of a compound of Formula I, or acomposition comprising the compound to soil, a plant, a part of a plant,foliage, roots, and/or seeds.

Additionally, another embodiment of the present disclosure is acomposition useful for protecting a plant against attack by aphytopathogenic organism and/or treatment of a plant infested by aphytopathogenic organism comprising a compound of Formula I and aphytologically acceptable carrier material.

In one embodiment, a compound of Formula (I) is provided:

wherein:

-   -   X is H or C(O)R₅;    -   Y is H, C(O)R₅, or Q;    -   Q is

-   -   R₁ is H, alkyl, alkenyl, aryl, —C(O)R₄, each optionally        substituted with one or more R₄;    -   R₂ is H, alkyl, alkenyl, aryl —C(O)R₄, each optionally        substituted with one or more R₄;    -   R₃ is H, —C(O)R₆ or —CH₂OC(O)R₆;    -   R₄ is alkyl, alkenyl, halo, haloalkyl, alkoxy, or aryl;    -   R₅ is alkyl, alkoxy, benzyl, benzyloxy, each optionally        substituted with one or more R₇, wherein each R₇ may be        optionally substituted with one or more R₄;    -   R⁶ is alkyl or alkoxy, each optionally substituted with one or        more R₄;    -   R⁷ is alkyl, alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl,        carbocyclic, heterocyclic, and—Si(R₄)₃, —C(O)R₄, —S(O)_(n)R₄,        each optionally substituted with one or more R⁴;    -   with the proviso that when R₁ and R₂ are H, X and Y are C(O)R₅        and R₅ is tert-butoxy.

In one more particular embodiment, X and Y are independently chosen fromH or C(O)R₅. In an even more particular embodiment, X and Y are C(O)R₅and R₅ is independently chosen from alkyl, alkoxy, benzyl, or benzyloxy,each optionally substituted with one or more R₇, wherein each R₇ may beoptionally substituted with one or more R⁴. In a still more particularembodiment, R₁ and R₂ are independently chosen from H, alkyl, alkenyl,aryl, or —C(O)R₄, each optionally substituted with one or more R₄.

In one embodiment, R₅ is alkoxy and R₁ and R₂ are H.

In one embodiment, R₅ is tert-butoxy. In one embodiment, X and Y arehydrogen. In a more particular embodiment, R₁ and R₂ are independentlychosen from H, alkyl, alkenyl, aryl, or —C(O)R₄, each optionallysubstituted with one or more R₄.

In one embodiment, R₁ and R₂ are independently alkyl, alkenyl, aryl, or—C(O)R₄, each optionally substituted with one or more R₄.

In one embodiment, R₁ and R₂ are independently alkyl or aryl, eachoptionally substituted with one or more R₄.

In one embodiment, the amine is protonated to give an ammonium salt of amineral acid independently chosen from hydrogen chloride, hydrogenbromide, or hydrogen iodide. In a more particular embodiment, theammonium salt is the ammonium hydrochloride.

In one embodiment, X is H and Y is Q.

In one embodiment, R₁ and R₂ are independently chosen from H, alkyl,alkenyl, aryl, or —C(O)R₄, each optionally substituted with one or moreR₄.

In one embodiment, R₁ and R₂ are independently alkyl, alkenyl, aryl, or—C(O)R₄, each optionally substituted one or more R₄.

In one embodiment, R₁ and R₂ are independently alkyl or aryl, eachoptionally substituted with one or more R₄.

In one embodiment, R₃ is H, —C(O)R₆ or —CH₂C(O)R₆. In a more particularembodiment, R₃ is H. In another more particular embodiment, R₃ isC(O)R₆. In a further particular embodiment, R₆ is alkyl or alkoxy, eachoptionaly substituted with one or more R₄. In another further particularembodiment, R₆ is alkyl, optionally substituted with one or more R₄. Instill another further particular embodiment, R₆ is —CH₃ or —CH₂CH₂—R₄and R₄ is OCH₃. In another more particular embodiment, R₃ is—CH₂OC(O)R₆. In a further particular embodiment, R₆ is alkyl or alkoxy,each optionally substituted with one or more R₄. In another furtherparticular embodiment, R₆ is alkyl, each optionally substituted with oneor more R₄. In still another more particular embodiment, R₆ is —CH₃ or—CH(CH₃)₂.

In one embodiment, a composition is provided for the control of a fungalor fugal like pathogen. In one embodiment, the composition includes thecompound of Formula I as defined by any of the above embodiments and aphytologically acceptable carrier material. The combination of Formula Iand the carrier is useful for the control of fungal and fungal likepathogens. In a more particular embodiment, the fungal or fungal likepathogen is selected from the group consisting of: Mycosphaerellagraminicola(Septoria tritici), Puccinia triticina, Puccinia striiformis,Venturia inaequalis, Uncinula necator, Rhynchosporium secalis,Magnaporthe grisea, Phakopsora pachyrhizi, Leptosphaeria nodorum,Blumeria graminis f sp. tritici, Blumeria graminis f sp. hordei,Erysiphe cichoracearum, Glomerella lagenarium, Cercospora beticola, andAlternaria solani. In a further particular embodiment, the fungalpathogen or fungal like pathogen is selected from the group consistingof: Septoria tritici and Puccinia triticina.

In one embodiment, a method for the control and prevention of plantdisease is provided. The method includes applying a fungicidallyeffective amount of at least one of the compounds of Formula I asdefined by any of the above embodiments to at least one surface selectedfrom the group consisting of: at least one surface of a plant, an areaadjacent to a plant, soil in contact with a plant, soil adjacent to aplant, seeds, and equipment for use in agriculture. In a more particularembodiment, the fungicidally effective amount Formula I is applied to asurface in the range of about 0.01 g/m² to about 0.45 g/m² of Formula I.

DESCRIPTION

The compounds of the present disclosure may be applied by any of avariety of known techniques, either as the compounds or as formulationscomprising the compounds. For example, the compounds may be applied tothe roots, seeds or foliage of plants for the control of various fungi,without damaging the commercial value of the plants. The materials maybe applied in the form of any of the generally used formulation types,for example, as solutions, dusts, wettable powders, flowableconcentrate, suspension concentrates, or emulsifiable concentrates.

Preferably, the compounds of the present disclosure are applied in theform of a formulation, comprising one or more of the compounds ofFormula I with a phytologically acceptable carrier. Concentratedformulations may be dispersed in water, or other liquids, forapplication, or formulations may be dust-like or granular, which maythen be applied without further treatment. The formulations may beprepared according to procedures that are conventional in theagricultural chemical art.

The present disclosure contemplates all vehicles by which one or more ofthe compounds may be formulated for delivery and use as a fungicide.Typically, formulations are applied as aqueous suspensions or emulsions.Such suspensions or emulsions may be produced from water-soluble,water-suspendible, or emulsifiable formulations which are solids,usually known as wettable powders; or liquids, usually known asemulsifiable concentrates, aqueous suspensions, or suspensionconcentrates. As will be readily appreciated, any material to whichthese compounds may be added may be used, provided it yields the desiredutility without significant interference with the activity of thesecompounds as antifungal agents.

Wettable powders, which may be compacted to form water-dispersiblegranules, comprise an intimate mixture of one or more of the compoundsof Formula I, an inert carrier and surfactants. The concentration of thecompound in the wettable powder may be from about 10 percent to about 90percent by weight based on the total weight of the wettable powder, morepreferably about 25 weight percent to about 75 weight percent. In thepreparation of wettable powder formulations, the compounds may becompounded with any finely divided solid, such as prophyllite, talc,chalk, gypsum, Fuller's earth, bentonite, attapulgite, starch, casein,gluten, montmorillonite clays, diatomaceous earths, purified silicatesor the like. In such operations, the finely divided carrier andsurfactants are typically blended with the compound(s) and milled.

Emulsifiable concentrates of the compounds of Formula I may comprise aconvenient concentration, such as from about 1 weight percent to about50 weight percent of the compound, in a suitable liquid, based on thetotal weight of the concentrate. The compounds may be dissolved in aninert carrier, which is either a water-miscible solvent or a mixture ofwater-immiscible organic solvents, and emulsifiers. The concentrates maybe diluted with water and oil to form spray mixtures in the form ofoil-in-water emulsions. Useful organic solvents include aromatics,especially the high-boiling naphthalenic and olefinic portions ofpetroleum such as heavy aromatic naphtha. Other organic solvents mayalso be used, for example, terpenic solvents, including rosinderivatives, aliphatic ketones, such as cyclohexanone, and complexalcohols, such as 2-ethoxyethanol.

Emulsifiers which may be advantageously employed herein may be readilydetermined by those skilled in the art and include various nonionic,anionic, cationic and amphoteric emulsifiers, or a blend of two or moreemulsifiers. Examples of nonionic emulsifiers useful in preparing theemulsifiable concentrates include the polyalkylene glycol ethers andcondensation products of alkyl and aryl phenols, aliphatic alcohols,aliphatic amines or fatty acids with ethylene oxide, propylene oxidessuch as the ethoxylated alkyl phenols and carboxylic esters solubilizedwith the polyol or polyoxyalkylene. Cationic emulsifiers includequaternary ammonium compounds and fatty amine salts. Anionic emulsifiersinclude the oil-soluble salts (e.g., calcium) of alkylaryl sulphonicacids, oil-soluble salts or sulfated polyglycol ethers and appropriatesalts of phosphated polyglycol ether.

Representative organic liquids which may be employed in preparing theemulsifiable concentrates of the compounds of the present disclosure arethe aromatic liquids such as xylene, propyl benzene fractions; or mixednaphthalene fractions, mineral oils, substituted aromatic organicliquids such as dioctyl phthalate; kerosene; dialkyl amides of variousfatty acids, particularly the dimethyl amides of fatty glycols andglycol derivatives such as the n-butyl ether, ethyl ether or methylether of diethylene glycol, the methyl ether of triethylene glycol,petroleum fractions or hydrocarbons such as mineral oil, aromaticsolvents, paraffinic oils, and the like; vegetable oils such as soy beanoil, rape seed oil, olive oil, castor oil, sunflower seed oil, coconutoil, corn oil, cotton seed oil, linseed oil, palm oil, peanut oil,safflower oil, sesame oil, tung oil and the like; esters of the abovevegetable oils; and the like. Mixtures of two or more organic liquidsmay also be employed in the preparation of the emulsifiable concentrate.Organic liquids include xylene, and propyl benzene fractions, withxylene being most preferred in some cases. Surface-active dispersingagents are typically employed in liquid formulations and in an amount offrom 0.1 to 20 percent by weight based on the combined weight of thedispersing agent with one or more of the compounds. The formulations canalso contain other compatible additives, for example, plant growthregulators and other biologically active compounds used in agriculture.

Aqueous suspensions comprise suspensions of one or more water-insolublecompounds of Formula I, dispersed in an aqueous vehicle at aconcentration in the range from about 1 to about 50 weight percent,based on the total weight of the aqueous suspension. Suspensions areprepared by finely grinding one or more of the compounds, and vigorouslymixing the ground material into a vehicle comprised of water andsurfactants chosen from the same types discussed above. Othercomponents, such as inorganic salts and synthetic or natural gums, mayalso be added to increase the density and viscosity of the aqueousvehicle.

The compounds of Formula I can also be applied as granular formulations,which are particularly useful for applications to the soil. Granularformulations generally contain from about 0.5 to about 10 weightpercent, based on the total weight of the granular formulation of thecompound(s), dispersed in an inert carrier which consists entirely or inlarge part of coarsely divided inert material such as attapulgite,bentonite, diatomite, clay or a similar inexpensive substance. Suchformulations are usually prepared by dissolving the compounds in asuitable solvent and applying it to a granular carrier which has beenpreformed to the appropriate particle size, in the range of from about0.5 to about 3 mm. A suitable solvent is a solvent in which the compoundis substantially or completely soluble. Such formulations may also beprepared by making a dough or paste of the carrier and the compound andsolvent, and crushing and drying to obtain the desired granularparticle.

Dusts containing the compounds of Formula I may be prepared byintimately mixing one or more of the compounds in powdered form with asuitable dusty agricultural carrier, such as, for example, kaolin clay,ground volcanic rock, and the like. Dusts can suitably contain fromabout 1 to about 10 weight percent of the compounds, based on the totalweight of the dust.

The formulations may additionally contain adjuvant surfactants toenhance deposition, wetting and penetration of the compounds onto thetarget crop and organism. These adjuvant surfactants may optionally beemployed as a component of the formulation or as a tank mix. The amountof adjuvant surfactant will typically vary from 0.01 to 1.0 percent byvolume, based on a spray-volume of water, preferably 0.05 to 0.5 volumepercent. Suitable adjuvant surfactants include, but are not limited toethoxylated nonyl phenols, ethoxylated synthetic or natural alcohols,salts of the esters or sulphosuccinic acids, ethoxylatedorganosilicones, ethoxylated fatty amines, blends of surfactants withmineral or vegetable oils, crop oil concentrate (mineral oil (85%)+emulsifiers (15%)); nonylphenol ethoxylate; benzylcocoalkyldimethylquaternary ammonium salt; blend of petroleum hydrocarbon, alkyl esters,organic acid, and anionic surfactant; C₉-C₁₁ alkylpolyglycoside;phosphated alcohol ethoxylate; natural primary alcohol (C₁₂-C₁₆)ethoxylate; di-sec-butylphenol EO-PO block copolymer;polysiloxane-methyl cap; nonylphenol ethoxylate +urea ammonium nitrate;emulsified methylated seed oil; tridecyl alcohol (synthetic) ethoxylate(8EO); tallow amine ethoxylate (15 EO); PEG(400) dioleate-99. Theformulations may also include oil-in-water emulsions such as thosedisclosed in U.S. patent application Ser. No. 11/495,228, the disclosureof which is expressly incorporated by reference herein.

The formulations may optionally include combinations that contain otherpesticidal compounds. Such additional pesticidal compounds may befungicides, insecticides, herbicides, nematocides, miticides,arthropodicides, bactericides or combinations thereof that arecompatible with the compounds of the present disclosure in the mediumselected for application, and not antagonistic to the activity of thepresent compounds. Accordingly, in such embodiments, the otherpesticidal compound is employed as a supplemental toxicant for the sameor for a different pesticidal use. The compounds of Formula I and thepesticidal compound in the combination can generally be present in aweight ratio of from 1:100 to 100:1.

The compounds of the present disclosure may also be combined with otherfungicides to form fungicidal mixtures and synergistic mixtures thereof.The fungicidal compounds of the present disclosure are often applied inconjunction with one or more other fungicides to control a wider varietyof undesirable diseases. When used in conjunction with otherfungicide(s), the presently claimed compounds may be formulated with theother fungicide(s), tank-mixed with the other fungicide(s) or appliedsequentially with the other fungicide(s). Such other fungicides mayinclude 2-(thiocyanatomethylthio)-benzothiazole, 2-phenylphenol,8-hydroxyquinoline sulfate, ametoctradin, amisulbrom, antimycin,Ampelomyces quisqualis, azaconazole, azoxystrobin, Bacillus subtilis,Bacillus subtilis strain QST713, benalaxyl, benomyl,benthiavalicarb-isopropyl, benzylaminobenzene-sulfonate (BABS) salt,bicarbonates, biphenyl, bismerthiazol, bitertanol, bixafen,blasticidin-S, borax, Bordeaux mixture, boscalid, bromuconazole,bupirimate, calcium polysulfide, captafol, captan, carbendazim,carboxin, carpropamid, carvone, chlazafenone, chloroneb, chlorothalonil,chlozolinate, Coniothyrium minitans, copper hydroxide, copper octanoate,copper oxychloride, copper sulfate, copper sulfate (tribasic), cuprousoxide, cyazofamid, cyflufenamid, cymoxanil, cyproconazole, cyprodinil,dazomet, debacarb, diammonium ethylenebis-(dithiocarbamate),dichlofluanid, dichlorophen, diclocymet, diclomezine, dichloran,diethofencarb, difenoconazole, difenzoquat ion, diflumetorim,dimethomorph, dimoxystrobin, diniconazole, diniconazole-M, dinobuton,dinocap, diphenylamine, dithianon, dodemorph, dodemorph acetate, dodine,dodine free base, edifenphos, enestrobin, enestroburin, epoxiconazole,ethaboxam, ethoxyquin, etridiazole, famoxadone, fenamidone, fenarimol,fenbuconazole, fenfuram, fenhexamid, fenoxanil, fenpiclonil,fenpropidin, fenpropimorph, fenpyrazamine, fentin, fentin acetate,fentin hydroxide, ferbam, ferimzone, fluazinam, fludioxonil, flumorph,fluopicolide, fluopyram, fluoroimide, fluoxastrobin, fluquinconazole,flusilazole, flusulfamide, flutianil, flutolanil, flutriafol,fluxapyroxad, folpet, formaldehyde, fosetyl, fosetyl-aluminium,fuberidazole, furalaxyl, furametpyr, guazatine, guazatine acetates,GY-81, hexachlorobenzene, hexaconazole, hymexazol, imazalil, imazalilsulfate, imibenconazole, iminoctadine, iminoctadine triacetate,iminoctadine tris(albesilate), iodocarb, ipconazole, ipfenpyrazolone,iprobenfos, iprodione, iprovalicarb, isoprothiolane, isopyrazam,isotianil, kasugamycin, kasugamycin hydrochloride hydrate,kresoxim-methyl, laminarin, mancopper, mancozeb, mandipropamid, maneb,mefenoxam, mepanipyrim, mepronil, meptyl-dinocap, mercuric chloride,mercuric oxide, mercurous chloride, metalaxyl, metalaxyl-M, metam,metam-ammonium, metam-potassium, metam-sodium, metconazole,methasulfocarb, methyl iodide, methyl isothiocyanate, metiram,metominostrobin, metrafenone, mildiomycin, myclobutanil, nabam,nitrothal-isopropyl, nuarimol, octhilinone, ofurace, oleic acid (fattyacids), orysastrobin, oxadixyl, oxine-copper, oxpoconazole fumarate,oxycarboxin, pefurazoate, penconazole, pencycuron, penflufen,pentachlorophenol, pentachlorophenyl laurate, penthiopyrad,phenylmercury acetate, phosphonic acid, phthalide, picoxystrobin,polyoxin B, polyoxins, polyoxorim, potassium bicarbonate, potassiumhydroxyquinoline sulfate, probenazole, prochloraz, procymidone,propamocarb, propamocarb hydrochloride, propiconazole, propineb,proquinazid, prothioconazole, pyraclostrobin, pyrametostrobin,pyraoxystrobin, pyrazophos, pyribencarb, pyributicarb, pyrifenox,pyrimethanil, pyriofenone, pyroquilon, quinoclamine, quinoxyfen,quintozene, Reynoutria sachalinensis extract, sedaxane, silthiofam,simeconazole, sodium 2-phenylphenoxide, sodium bicarbonate, sodiumpentachlorophenoxide, spiroxamine, sulfur, SYP-Z048, tar oils,tebuconazole, tebufloquin, tecnazene, tetraconazole, thiabendazole,thifluzamide, thiophanate-methyl, thiram, tiadinil, tolclofos-methyl,tolylfluanid, triadimefon, triadimenol, triazoxide, tricyclazole,tridemorph, trifloxystrobin, triflumizole, triforine, triticonazole,validamycin, valifenalate, valiphenal, vinclozolin, zineb, ziram,zoxamide, Candida oleophila, Fusarium oxysporum, Gliocladium spp.,Phlebiopsis gigantea, Streptomyces griseoviridis, Trichoderma spp.,(RS)-N-(3,5-dichlorophenyl)-2-(methoxymethyl)-succinimide,1,2-dichloropropane, 1,3-dichloro-1,1,3,3-tetrafluoroacetone hydrate,1-chloro-2,4-dinitronaphthalene, 1-chloro-2-nitropropane,2-(2-heptadecyl-2-imidazolin-1-yl)ethanol,2,3-dihydro-5-phenyl-1,4-dithi-ine 1,1,4,4-tetraoxide,2-methoxyethylmercury acetate, 2-methoxyethylmercury chloride,2-methoxyethylmercury silicate, 3-(4-chlorophenyl)-5-methylrhodanine,4-(2-nitroprop-1-enyl)phenyl thiocyanateme, ampropylfos, anilazine,azithiram, barium polysulfide, Bayer 32394, benodanil, benquinox,bentaluron, benzamacril; benzamacril-isobutyl, benzamorf, binapacryl,bis(methylmercury) sulfate, bis(tributyltin) oxide, buthiobate, cadmiumcalcium copper zinc chromate sulfate, carbamorph, CECA, chlobenthiazone,chloraniformethan, chlorfenazole, chlorquinox, climbazole, copperbis(3-phenylsalicylate), copper zinc chromate, cufraneb, cuprichydrazinium sulfate, cuprobam, cyclafuramid, cypendazole, cyprofuram,decafentin, dichlone, dichlozoline, diclobutrazol, dimethirimol,dinocton, dinosulfon, dinoterbon, dipyrithione, ditalimfos, dodicin,drazoxolon, EBP, ESBP, etaconazole, etem, ethirim, fenaminosulf,fenapanil, fenitropan, fluotrimazole, furcarbanil, furconazole,furconazole-cis, furmecyclox, furophanate, glyodine, griseofulvin,halacrinate, Hercules 3944, hexylthiofos, ICIA0858, isopamphos,isovaledione, mebenil, mecarbinzid, metazoxolon, methfuroxam,methylmercury dicyandiamide, metsulfovax, milneb, mucochloric anhydride,myclozolin, N-3,5-dichlorophenyl succinimide,N-3-nitrophenylitaconimide, natamycin,N-ethylmercurio-4-toluenesulfonanilide, nickelbis(dimethyldithiocarbamate), OCH, phenylmercurydimethyldithiocarbamate, phenylmercury nitrate, phosdiphen, prothiocarb;prothiocarb hydrochloride, pyracarbolid, pyridinitril, pyroxychlor,pyroxyfur, quinacetol; quinacetol sulfate, quinazamid, quinconazole,rabenzazole, salicylanilide, SSF-109, sultropen, tecoram, thiadifluor,thicyofen, thiochlorfenphim, thiophanate, thioquinox, tioxymid,triamiphos, triarimol, triazbutil, trichlamide, urbacid, zarilamid, andany combinations thereof.

Additionally, the compounds described herein may be combined with otherpesticides, including insecticides, nematocides, miticides,arthropodicides, bactericides or combinations thereof that arecompatible with the compounds of the present disclosure in the mediumselected for application, and not antagonistic to the activity of thepresent compounds to form pesticidal mixtures and synergistic mixturesthereof. The fungicidal compounds of the present disclosure may beapplied in conjunction with one or more other pesticides to control awider variety of undesirable pests. When used in conjunction with otherpesticides, the presently claimed compounds may be formulated with theother pesticide(s), tank-mixed with the other pesticide(s) or appliedsequentially with the other pesticide(s). Typical insecticides include,but are not limited to: 1,2-dichloropropane, abamectin, acephate,acetamiprid, acethion, acetoprole, acrinathrin, acrylonitrile,alanycarb, aldicarb, aldoxycarb, aldrin, allethrin, allosamidin,allyxycarb, alpha-cypermethrin, alpha-ecdysone, alpha-endosulfan,amidithion, aminocarb, amiton, amiton oxalate, amitraz, anabasine,athidathion, azadirachtin, azamethiphos, azinphos-ethyl,azinphos-methyl, azothoate, barium hexafluorosilicate, barthrin,bendiocarb, benfuracarb, bensultap, beta-cyfluthrin, beta-cypermethrin,bifenthrin, bioallethrin, bioethanomethrin, biopermethrin, bistrifluron,borax, boric acid, bromfenvinfos, bromocyclen, bromo-DDT, bromophos,bromophos-ethyl, bufencarb, buprofezin, butacarb, butathiofos,butocarboxim, butonate, butoxycarboxim, cadusafos, calcium arsenate,calcium polysulfide, camphechlor, carbanolate, carbaryl, carbofuran,carbon disulfide, carbon tetrachloride, carbophenothion, carbosulfan,cartap, cartap hydrochloride, chlorantraniliprole, chlorbicyclen,chlordane, chlordecone, chlordimeform, chlordimeform hydrochloride,chlorethoxyfos, chlorfenapyr, chlorfenvinphos, chlorfluazuron,chlormephos, chloroform, chloropicrin, chlorphoxim, chlorprazophos,chlorpyrifos, chlorpyrifos-methyl, chlorthiophos, chromafenozide,cinerin I, cinerin II, cinerins, cismethrin, cloethocarb, closantel,clothianidin, copper acetoarsenite, copper arsenate, copper naphthenate,copper oleate, coumaphos, coumithoate, crotamiton, crotoxyphos,crufomate, cryolite, cyanofenphos, cyanophos, cyanthoate,cyantraniliprole, cyclethrin, cycloprothrin, cyfluthrin, cyhalothrin,cypermethrin, cyphenothrin, cyromazine, cythioate, DDT, decarbofuran,deltamethrin, demephion, demephion-O, demephion-S, demeton,demeton-methyl, demeton-O, demeton-O-methyl, demeton-S,demeton-S-methyl, demeton-S-methylsulphon, diafenthiuron, dialifos,diatomaceous earth, diazinon, dicapthon, dichlofenthion, dichlorvos,dicresyl, dicrotophos, dicyclanil, dieldrin, diflubenzuron, dilor,dimefluthrin, dimefox, dimetan, dimethoate, dimethrin, dimethylvinphos,dimetilan, dinex, dinex-diclexine, dinoprop, dinosam, dinotefuran,diofenolan, dioxabenzofos, dioxacarb, dioxathion, di sulfoton,dithicrofos, d-limonene, DNOC, DNOC-ammonium, DNOC-potassium,DNOC-sodium, doramectin, ecdysterone, emamectin, emamectin benzoate,EMPC, empenthrin, endosulfan, endothion, endrin, EPN, epofenonane,eprinomectin, esdepalléthrine, esfenvalerate, etaphos, ethiofencarb,ethion, ethiprole, ethoate-methyl, ethoprophos, ethyl formate,ethyl-DDD, ethylene dibromide, ethylene dichloride, ethylene oxide,etofenprox, etrimfos, EXD, famphur, fenamiphos, fenazaflor,fenchlorphos, fenethacarb, fenfluthrin, fenitrothion, fenobucarb,fenoxacrim, fenoxycarb, fenpirithrin, fenpropathrin, fensulfothion,fenthion, fenthion-ethyl, fenvalerate, fipronil, flonicamid,flubendiamide, flucofuron, flucycloxuron, flucythrinate, flufenerim,flufenoxuron, flufenprox, fluvalinate, fonofos, formetanate, formetanatehydrochloride, formothion, formparanate, formparanate hydrochloride,fosmethilan, fospirate, fosthietan, furathiocarb, furethrin,gamma-cyhalothrin, gamma-HCH, halfenprox, halofenozide, HCH, HEOD,heptachlor, heptenophos, heterophos, hexaflumuron, HHDN, hydramethylnon,hydrogen cyanide, hydroprene, hyquincarb, imidacloprid, imiprothrin,indoxacarb, iodomethane, IPSP, isazofos, isobenzan, isocarbophos,isodrin, isofenphos, isofenphos-methyl, isoprocarb, isoprothiolane,isothioate, isoxathion, ivermectin, jasmolin I, jasmolin II, jodfenphos,juvenile hormone I, juvenile hormone II, juvenile hormone III, kelevan,kinoprene, lambda-cyhalothrin, lead arsenate, lepimectin, leptophos,lindane, lirimfos, lufenuron, lythidathion, malathion, malonoben,mazidox, mecarbam, mecarphon, menazon, mephosfolan, mercurous chloride,mesulfenfos, metaflumizone, methacrifos, methamidophos, methidathion,methiocarb, methocrotophos, methomyl, methoprene, methoxychlor,methoxyfenozide, methyl bromide, methyl isothiocyanate,methylchloroform, methylene chloride, metofluthrin, metolcarb,metoxadiazone, mevinphos, mexacarbate, milbemectin, milbemycin oxime,mipafox, mirex, molosultap, monocrotophos, monomehypo, monosultap,morphothion, moxidectin, naftalofos, naled, naphthalene, nicotine,nifluridide, nitenpyram, nithiazine, nitrilacarb, novaluron,noviflumuron, omethoate, oxamyl, oxydemeton-methyl, oxydeprofos,oxydisulfoton, para-dichlorobenzene, parathion, parathion-methyl,penfluron, pentachlorophenol, permethrin, phenkapton, phenothrin,phenthoate, phorate, phosalone, phosfolan, phosmet, phosnichlor,phosphamidon, phosphine, phoxim, phoxim-methyl, pirimetaphos,pirimicarb, pirimiphos-ethyl, pirimiphos-methyl, potassium arsenite,potassium thiocyanate, pp′-DDT, prallethrin, precocene I, precocene II,precocene III, primidophos, profenofos, profluralin, promacyl,promecarb, propaphos, propetamphos, propoxur, prothidathion, prothiofos,prothoate, protrifenbute, pyraclofos, pyrafluprole, pyrazophos,pyresmethrin, pyrethrin I, pyrethrin II, pyrethrins, pyridaben,pyridalyl, pyridaphenthion, pyrifluquinazon, pyrimidifen, pyrimitate,pyriprole, pyriproxyfen, quassia, quinalphos, quinalphos-methyl,quinothion, rafoxanide, resmethrin, rotenone, ryania, sabadilla,schradan, selamectin, silafluofen, silica gel, sodium arsenite, sodiumfluoride, sodium hexafluorosilicate, sodium thiocyanate, sophamide,spinetoram, spinosad, spiromesifen, spirotetramat, sulcofuron,sulcofuron-sodium, sulfluramid, sulfotep, sulfoxaflor, sulfurylfluoride, sulprofos, tau-fluvalinate, tazimcarb, TDE, tebufenozide,tebufenpyrad, tebupirimfos, teflubenzuron, tefluthrin, temephos, TEPP,terallethrin, terbufos, tetrachloroethane, tetrachlorvinphos,tetramethrin, tetramethylfluthrin, theta-cypermethrin, thiacloprid,thiamethoxam, thicrofos, thiocarboxime, thiocyclam, thiocyclam oxalate,thiodicarb, thiofanox, thiometon, thiosultap, thiosultap-disodium,thiosultap-monosodium, thuringiensin, tolfenpyrad, tralomethrin,transfluthrin, transpermethrin, triarathene, triazamate, triazophos,trichlorfon, trichlormetaphos-3, trichloronat, trifenofos, triflumuron,trimethacarb, triprene, vamidothion, vaniliprole, XMC, xylylcarb,zeta-cypermethrin, zolaprofos, and any combinations thereof.

Additionally, the compounds described herein be combined with herbicidesthat are compatible with the compounds of the present disclosure in themedium selected for application, and not antagonistic to the activity ofthe present compounds to form pesticidal mixtures and synergisticmixtures thereof. The fungicidal compounds of the present disclosure maybe applied in conjunction with one or more herbicides to control a widevariety of undesirable plants. When used in conjunction with herbicides,the presently claimed compounds may be formulated with the herbicide(s),tank-mixed with the herbicide(s) or applied sequentially with theherbicide(s). Typical herbicides include, but are not limited to: 4-CPA;4-CPB; 4-CPP; 2,4-D; 3,4-DA; 2,4-DB; 3,4-DB; 2,4-DEB; 2,4-DEP; 3,4-DP;2,3,6-TBA; 2,4,5-T; 2,4,5-TB; acetochlor, acifluorfen, aclonifen,acrolein, alachlor, allidochlor, alloxydim, allyl alcohol, alorac,ametridione, ametryn, amibuzin, amicarbazone, amidosulfuron,aminocyclopyrachlor, aminopyralid, amiprofos-methyl, amitrole, ammoniumsulfamate, anilofos, anisuron, asulam, atraton, atrazine, azafenidin,azimsulfuron, aziprotryne, barban, BCPC, beflubutamid, benazolin,bencarbazone, benfluralin, benfuresate, bensulfuron, bensulide,bentazone, benzadox, benzfendizone, benzipram, benzobicyclon,benzofenap, benzofluor, benzoylprop, benzthiazuron, bicyclopyrone,bifenox, bilanafos, bispyribac, borax, bromacil, bromobonil,bromobutide, bromofenoxim, bromoxynil, brompyrazon, butachlor,butafenacil, butamifos, butenachlor, buthidazole, buthiuron, butralin,butroxydim, buturon, butylate, cacodylic acid, cafenstrole, calciumchlorate, calcium cyanamide, cambendichlor, carbasulam, carbetamide,carboxazole chlorprocarb, carfentrazone, CDEA, CEPC, chlomethoxyfen,chloramben, chloranocryl, chlorazifop, chlorazine, chlorbromuron,chlorbufam, chloreturon, chlorfenac, chlorfenprop, chlorflurazole,chlorflurenol, chloridazon, chlorimuron, chlornitrofen, chloropon,chlorotoluron, chloroxuron, chloroxynil, chlorpropham, chlorsulfuron,chlorthal, chlorthiamid, cinidon-ethyl, cinmethylin, cinosulfuron,cisanilide, clethodim, cliodinate, clodinafop, clofop, clomazone,clomeprop, cloprop, cloproxydim, clopyralid, cloransulam, CMA, coppersulfate, CPMF, CPPC, credazine, cresol, cumyluron, cyanatryn, cyanazine,cycloate, cyclosulfamuron, cycloxydim, cycluron, cyhalofop, cyperquat,cyprazine, cyprazole, cypromid, daimuron, dalapon, dazomet, delachlor,desmedipham, desmetryn, di-allate, dicamba, dichlobenil, dichloralurea,dichlormate, dichlorprop, dichlorprop-P, diclofop, diclosulam,diethamquat, diethatyl, difenopenten, difenoxuron, difenzoquat,diflufenican, diflufenzopyr, dimefuron, dimepiperate, dimethachlor,dimethametryn, dimethenamid, dimethenamid-P, dimexano, dimidazon,dinitramine, dinofenate, dinoprop, dinosam, dinoseb, dinoterb,diphenamid, dipropetryn, diquat, disul, dithiopyr, diuron, DMPA, DNOC,DSMA, EBEP, eglinazine, endothal, epronaz, EPTC, erbon, esprocarb,ethalfluralin, ethametsulfuron, ethidimuron, ethiolate, ethofumesate,ethoxyfen, ethoxysulfuron, etinofen, etnipromid, etobenzanid, EXD,fenasulam, fenoprop, fenoxaprop, fenoxaprop-P, fenoxasulfone,fenteracol, fenthiaprop, fentrazamide, fenuron, ferrous sulfate,flamprop, flamprop-M, flazasulfuron, florasulam, fluazifop, fluazifop-P,fluazolate, flucarbazone, flucetosulfuron, fluchloralin, flufenacet,flufenican, flufenpyr, flumetsulam, flumezin, flumiclorac, flumioxazin,flumipropyn, fluometuron, fluorodifen, fluoroglycofen, fluoromidine,fluoronitrofen, fluothiuron, flupoxam, flupropacil, flupropanate,flupyrsulfuron, fluridone, flurochloridone, fluroxypyr, flurtamone,fluthiacet, fomesafen, foramsulfuron, fosamine, furyloxyfen,glufosinate, glufosinate-P, glyphosate, halosafen, halosulfuron,haloxydine, haloxyfop, haloxyfop-P, hexachloroacetone, hexaflurate,hexazinone, imazamethabenz, imazamox, imazapic, imazapyr, imazaquin,imazethapyr, imazosulfuron, indanofan, indaziflam, iodobonil,iodomethane, iodosulfuron, ioxynil, ipazine, ipfencarbazone, iprymidam,isocarbamid, isocil, isomethiozin, isonoruron, isopolinate, isopropalin,isoproturon, isouron, isoxaben, isoxachlortole, isoxaflutole,isoxapyrifop, karbutilate, ketospiradox, lactofen, lenacil, linuron,MAA, MAMA, MCPA, MCPA-thioethyl, MCPB, mecoprop, mecoprop-P, medinoterb,mefenacet, mefluidide, mesoprazine, mesosulfuron, mesotrione, metam,metamifop, metamitron, metazachlor, metazosulfuron, metflurazon,methabenzthiazuron, methalpropalin, methazole, methiobencarb,methiozolin, methiuron, methometon, methoprotryne, methyl bromide,methyl isothiocyanate, methyldymron, metobenzuron, metobromuron,metolachlor, metosulam, metoxuron, metribuzin, metsulfuron, molinate,monalide, monisouron, monochloroacetic acid, monolinuron, monuron,morfamquat, MSMA, naproanilide, napropamide, naptalam, neburon,nicosulfuron, nipyraclofen, nitralin, nitrofen, nitrofluorfen,norflurazon, noruron, OCH, orbencarb, ortho-dichlorobenzene,orthosulfamuron, oryzalin, oxadiargyl, oxadiazon, oxapyrazon,oxasulfuron, oxaziclomefone, oxyfluorfen, parafluron, paraquat,pebulate, pelargonic acid, pendimethalin, penoxsulam, pentachlorophenol,pentanochlor, pentoxazone, perfluidone, pethoxamid, phenisopham,phenmedipham, phenmedipham-ethyl, phenobenzuron, phenylmercury acetate,picloram, picolinafen, pinoxaden, piperophos, potassium arsenite,potassium azide, potassium cyanate, pretilachlor, primisulfuron,procyazine, prodiamine, profluazol, profluralin, profoxydim,proglinazine, prometon, prometryn, propachlor, propanil, propaquizafop,propazine, propham, propisochlor, propoxycarbazone, propyrisulfuron,propyzamide, prosulfalin, prosulfocarb, prosulfuron, proxan, prynachlor,pydanon, pyraclonil, pyraflufen, pyrasulfotole, pyrazolynate,pyrazosulfuron, pyrazoxyfen, pyribenzoxim, pyributicarb, pyriclor,pyridafol, pyridate, pyriftalid, pyriminobac, pyrimisulfan, pyrithiobac,pyroxasulfone, pyroxsulam, quinclorac, quinmerac, quinoclamine,quinonamid, quizalofop, quizalofop-P, rhodethanil, rimsulfuron,saflufenacil, S-metolachlor, sebuthylazine, secbumeton, sethoxydim,siduron, simazine, simeton, simetryn, SMA, sodium arsenite, sodiumazide, sodium chlorate, sulcotrione, sulfallate, sulfentrazone,sulfometuron, sulfosulfuron, sulfuric acid, sulglycapin, swep, TCA,tebutam, tebuthiuron, tefuryltrione, tembotrione, tepraloxydim,terbacil, terbucarb, terbuchlor, terbumeton, terbuthylazine, terbutryn,tetrafluron, thenylchlor, thiazafluron, thiazopyr, thidiazimin,thidiazuron, thiencarbazone-methyl, thifensulfuron, thiobencarb,tiocarbazil, tioclorim, topramezone, tralkoxydim, triafamone,tri-allate, triasulfuron, triaziflam, tribenuron, tricamba, triclopyr,tridiphane, trietazine, trifloxysulfuron, trifluralin, triflusulfuron,trifop, trifopsime, trihydroxytriazine, trimeturon, tripropindan,tritac, tritosulfuron, vernolate, and xylachlor.

Another embodiment of the present disclosure is a method for the controlor prevention of fungal attack. This method comprises applying to thesoil, plant, roots, foliage, seed or locus of the fungus, or to a locusin which the infestation is to be prevented (for example applying tocereal or grape plants), a fungicidally effective amount of one or moreof the compounds of Formula I. The compounds are suitable for treatmentof various plants at fungicidal levels, while exhibiting lowphytotoxicity. The compounds may be useful both in a protectant and/oran eradicant fashion.

The compounds have been found to have significant fungicidal effectparticularly for agricultural use. Many of the compounds areparticularly effective for use with agricultural crops and horticulturalplants.

It will be understood by those in the art that the efficacy of thecompound for the foregoing fungi establishes the general utility of thecompounds as fungicides.

The compounds have broad ranges of activity against fungal pathogens.Exemplary pathogens may include, but are not limited to, causing agentof wheat leaf blotch (Mycosphaerella graminicola; impect stage: Septoriatritici), brown rust (Puccinia triticina), stripe rust (Pucciniastriiformis), scab of apple (Venturia inaequalis), blister smut of maize(Ustilago maydis), powdery mildew of grapevine (Uncinula necator), leafblotch of cereals (Rhynchosporium secalis), blast of rice (Magnaporthegrisea), downy mildew of cucurbits (Pseudoperonospora cubensis), rust ofsoybean (Phakopsora pachyrhizi), glume blotch of wheat (Leptosphaerianodorum), powdery mildew of wheat (Blumeria graminis f sp. tritici),powdery mildew of barley (Blumeria graminis f. sp. hordei), powderymildew of cucurbits (Erysiphe cichoracearum), anthracnose of cucurbits(Glomerella lagenarium), leaf spot of beet (Cercospora beticola), earlyblight of eggplant (Alternaria solani), and net blotch of barley(Pyrenophora teres). The exact amount of the active material to beapplied is dependent not only on the specific active material beingapplied, but also on the particular action desired, the fungal speciesto be controlled, and the stage of growth thereof, as well as the partof the plant or other product to be contacted with the compound. Thus,all the compounds, and formulations containing the same, may not beequally effective at similar concentrations or against the same fungalspecies.

The compounds are effective in use with plants in a disease-inhibitingand phytologically acceptable amount. The term “disease-inhibiting andphytologically acceptable amount” refers to an amount of a compound thatkills or inhibits the plant disease for which control is desired, but isnot significantly toxic to the plant. This amount will generally be fromabout 0.1 to about 1000 ppm (parts per million), with 1 to 500 ppm beingpreferred. The exact concentration of compound required varies with thefungal disease to be controlled, the type of formulation employed, themethod of application, the particular plant species, climate conditions,and the like. A suitable application rate is typically in the range fromabout 0.10 to about 4 pounds/acre (about 0.01 to 0.45 grams per squaremeter, g/m²). Fungicidally effective amount of the compounds includeamounts sufficient to kill or control true fungi, pseudo-fungi, andrelated organisms including water moulds.

Any range or desired value given herein may be extended or alteredwithout losing the effects sought, as is apparent to the skilled personfor an understanding of the teachings herein.

The compounds of Formula I may be made using well-known chemicalprocedures. Intermediates not specifically mentioned in this disclosureare either commercially available, may be made by routes disclosed inthe chemical literature, or may be readily synthesized from commercialstarting materials utilizing standard procedures.

General Schemes

The following schemes illustrate approaches to generating picolinamidecompounds of Formula (I). It may be understood by those skilled in theart that R₁ and R₂ may be differentially substituted through sequentialderivatizations, such as an arylation reaction followed by an allylationreaction. The following descriptions and examples are provided forillustrative purposes and should not be construed as limiting in termsof substituents or substitution patterns. The derivatizations thatresult in differential substitution at R₁ and R₂ are designated as“Derivatization Type^(n)”, wherein n=1 or 2. For example, “Arylation¹”indicates that the first derivatization performed is an arylationreaction and “Allylation²” denotes that the derivatization beingperformed second in the sequence is an allylation reaction.Additionally, this convention is applied to the structures throughoutthe schemes as well. For example, the structure below indicates that R₁is an aryl substituent that was installed as the first derivatization ofthe diol, i.e. R₁ and R₂ =H, and that R₂ is an allyl substituent thatwas installed as the second derivatization of a mono-substitutedalcohol, i.e. R₁=aryl and R₂=H.

Compounds of Formulas 1.6, 1.7, 1.8, 1.9, 1.10, and 1.11 (shown below),wherein R₅ are previously defined within the scope of this disclosure,may be prepared as shown in Scheme 1. In step a of Scheme 1, treatmentof a 3,4-dihydropyran of Formula 1.1, prepared as in Nicolaou, K. C. etal. J. Am. Chem. Soc., 2004, 126, 6234-6235, with ozone in the presenceof a base, such as sodium bicarbonate (NaHCO₃), in a mixture of ahalogenated solvent such as dichloromethane (CH₂Cl₂) and an alcoholicsolvent such as methanol (MeOH), followed by treatment with a biphasicmixture of an aqueous solution of a base, such as LiOH, and a polaraprotic solvent such as tetrahydrofuran (THF) provides the compound ofFormula 1.2. In step b of Scheme 1, the compound of Formula 1.2 may betreated with an ylide, such as that which is generated frommethyltriphenyl phosphonium bromide and a base such as n-butyl lithium,to produce a compound of Formula 1.3. In step c of Scheme 1, thecompound of Formula 1.3 may be protected as an ester, such as anacetate, by treating with an acylating agent such as acetyl chloride oracetic anhydride in the presence of an organic base, such astriethylamine (TEA), in a halogenated solvent, such as CH₂Cl₂, to afforda compound of Formula 1.4. In step d of Scheme 1, the compound ofFormula 1.4 may be treated with an alkylborane reagent, such as9-borabicyclo[3.3.1]nonane (9-BBN), in a polar aprotic solvent such asTHF, at a temperature between ambient temperature and 50° C. Treatmentof the resulting mixture between ambient temperature and 55° C. with anaqueous solution of a base, such as potassium phosphate, a brominatedolefin, such as the compound of Formula 1.5, wherein R5 is tert-butoxy,prepared as in Singh, Janak et al. Organic Letters, 2003, 5(17),3155-3158, and a catalyst, such as [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (PdCl₂(dppf) affords the compound of Formula 1.6.In step e of Scheme 1, treatment of the compound of Formula 1.6 withhydrogen (15-200 psi) in the presence of a catalyst, such as1,2-bis[(2S,5S)-2,5-diethyl-phospholano]benzene(1,5-cyclooctadiene)rhodium(I)trifluoromethanesulfonate ((S,S)-Et-DUPHOS-Rh), in an alcoholic solventsuch as MeOH, afforded a compound of Formula 1.7. In step f of Scheme 1,treatment of the compound of Formula 1.7 with a base such as lithiumhydroxide (LiOH) in a mixture of water and an alcoholic solvent such asMeOH produced a compound of Formula 1.8. In step g of Scheme 1, asolution of a compound of Formula 1.8 in a halogenated solvent such asCH₂Cl₂ or an aromatic solvent such as toluene may be added over a periodof 4-12 hours (h) to a mixture of a base such as 4-dimethylaminopyridine(DMAP) and an anhydride such as 2-methyl-6-nitrobenzoic anhydride (MNBA)in either a halogenated solvent such as CH₂Cl₂ or an aromatic solventsuch as toluene to generate a compound of Formula 1.9. In step h ofScheme 1, a compound of Formula 1.9 may be protected with a group suchas a carbamate, for example a tert-butylcarbamate, by treating with analkyl, alkylaryl, haloalkyl, or an aryl dicarbonate such asdi-tert-butyl dicarbonate in the presence of a base, such as DMAP, in apolar aprotic solvent such as acetonitrile (CH₃CN), to afford a compoundof Formula 1.10. In step i of Scheme 1, treatment of a solution of acompound of Formula 1.10 in a solvent such as ethyl acetate (EtOAc) withhydrogen gas (15-55 psi) in the presence of a palladium catalyst, suchas 5% or 10% w/w palladium on carbon (Pd/C), affords a compound ofFormula 1.11.

Arylation⁽¹⁾

Phenoxy compounds of Formulas 2.1, 2.2, and 2.3, wherein R₁, R₂, and R₅are previously defined within the scope of this disclosure, may beprepared as shown in step a of Scheme 2. In step a, treatment of abis-carbamate protected amine of Formula 1.11, such as the bistert-butylcarbamate, wherein R₁ and R₂ are hydrogen, with atriarylbismuth reagent, prepared according to the methods described byHassan, A. et. al. Organometallics 1996, 15, 5613-5621, Moiseev, D. V.et al. J. Organomet. Chem. 2005, 690, 3652-3663, or Sinclair, P. J. etal. Bioorg. Med. Chem. Lett. 1995, 5, 1035-1038, in the presence of acopper catalyst, for example diacetoxycopper, and an aromatic solventsuch as toluene at ambient or an elevated temperature, such as 40° C.,affords a mixture of the arylated products of Formulas 2.1, 2.2, and2.3.

Allylation⁽¹⁾

Alkoxy compounds of Formulas 3.4, 3.5, and 3.6, wherein R₁, R₂, and R₅are previously defined within the scope of this disclosure, may beprepared as shown in steps a and b of Scheme 3. In step a, treatment ofa bis-carbamate protected amine of Formula 1.11, such as the bistert-butylcarbamate, wherein R₁ and R₂ are hydrogen, with an allylcarbonate, such as a tert-butyl (allyl) carbonate or a symmetric (allyl)carbonate, such as bis (2-methallyl) carbonate, in the presence of apalladium catalyst and ligand, for exampletris(dibenzylideneacetone)dipalladium(0) (Pd₂(dba)₃) and1,1′-bis(diphenylphosphino)-ferrocene (dppf), in a polar aprotic solventlike THF at an elevated temperature, such as 60° C., affords a mixtureof the allyloxy products of Formulas 3.1, 3.2, and 3.3. Subsequently,the allyloxy compounds may be reduced, as shown in step b, to thecorresponding alkoxy compounds of Formulas 3.4, 3.5, and 3.6, whereinR₁, R₂, and R₅ are previously defined, under standard catalytichydrogenation conditions. For example, stirring solutions of compoundsof Formulas 3.1, 3.2, or 3.3 in a solvent like EtOAc with a palladiumcatalyst, such as 5% or 10% w/w Pd/C, under an atmosphere of hydrogenaffords the alkoxy compounds of Formulas 3.4, 3.5, and 3.6. In step c,mono-substituted compounds of Formulas 3.3 or 3.6 may be treated with analkylating reagent, such as trimethyloxonium tetrafluroborate, in thepresence of a base, such as Proton Sponge®, in a solvent such as CH₂Cl₂to afford the di-substituted compounds of Formula 3.7, wherein R₁, R₂,and R₅ are as previously defined. Compounds of Formula 3.7, where R₂ isallyl, may be subsequently reduced under the conditions previouslydisclosed in step b to afford compounds of Formula 3.5.

Acylation⁽¹⁾

Acyloxy compounds of Formula 4.1, wherein R₁, R₂, and R₅ are previouslydefined herein, may be prepared as shown in step a of Scheme 4. In stepa, treatment of a solution of a bis-carbamate protected amine of Formula1.11, such as the bis tert-butylcarbamate, wherein R₁ and R₂ arehydrogen, with a base such as 4-dimethylaminopyridine (DMAP) in asolvent such as CH₂Cl₂, followed by treatment with an acid chlorideaffords the acyloxy compound of Formula 4.1.

Arylation⁽²⁾

Disubstituted compounds of Formula 5.3 and 5.4, wherein R₁, R₂, and R₅are previously defined within the scope of this disclosure, may beprepared as illustrated in step a of Scheme 5. Arylation of abis-carbamate protected amine, such as the bis tert-butylcarbamate, ofthe isomeric monosubstituted compounds of Formulas 5.1 and 5.2, whereinR₂ is hydrogen and R₁ is hydrogen respectively, may be accomplishedusing the copper catalyzed triarylbismuth conditions previouslydisclosed in step a of Scheme 2.

Allylation⁽²⁾

Disubstituted compounds of Formula 6.3, 6.4, 6.5, and 6.6, wherein R₁,R₂, and R₅ are previously defined within the scope of this disclosure,may be prepared as illustrated in steps a and b of Scheme 6. Allylationof a bis-carbamate protected amine, such as the bis tert-butylcarbamate,of the isomeric monosubstituted compounds of Formulas 6.1 and 6.2,wherein R₂ is hydrogen and R₁ is hydrogen respectively, may beaccomplished using the palladium catalyzed allylation conditionspreviously disclosed in step a of Scheme 3 to give the disubstitutedcompounds of Formula 6.3 and 6.4, wherein R₁, R₂, and R₅ are previouslydefined. Subsequent palladium catalyzed hydrogenation of compounds ofFormulas 6.3 and 6.4, as previously disclosed in step b of Scheme 3,affords compounds of Formulas 6.5 and 6.6. Alternatively, disubstitutedcompounds of Formula 6.5 and 6.6, wherein R₁, R₂, and R₅ are previouslydefined, can be obtained from monosubstituted compounds of Formulas 6.1and 6.2, wherein R₂ is hydrogen and R₁ is hydrogen respectively, viadirect alkylation as disclosed in step c of Scheme 3.

Acylation⁽²⁾

Disubstituted compounds of Formulas 7.3 and 7.4, wherein R₁, R₂, and R₅are previously defined herein, may be prepared as illustrated in step aof Scheme 7. Acylation of a bis-carbamate protected amine, such as thebis tert-butylcarbamate, of the isomeric monosubstituted compounds ofFormulas 7.1 and 7.2, wherein R₂ is hydrogen and R₁ is hydrogenrespectively, may be accomplished by treating solutions of the compoundsin CH₂Cl₂ with an organic base, such as pyridine, followed by treatmentwith an acid chloride to give the disubstituted compounds of Formulas7.3 and 7.4, wherein R₁, R₂, and R₅ are previously defined.

Conjugate Addition

Disubstituted compounds of Formulas 8.7 and 8.8, wherein R₁, R₂, and R₅are previously defined within the scope of this disclosure, may beprepared as illustrated in steps a, b, and c of Scheme 8. Addition of abis-carbamate protected amine, such as the bis tert-butylcarbamate, ofthe isomeric monosubstituted compounds of Formulas 8.1 and 8.2, whereinR₂ and R₁ are hydrogen respectively, into conjugated alkynes, such asbut-3-yn-2-one, may be accomplished by treating solutions of thecompounds in a solvent such as CH₂Cl₂ with a catalytic amount of1,4-diazabicyclo[2.2.2]octane (DABCO), followed by addition of theconjugated alkyne at a reduced temperature, for example 0° C., to affordmixtures of E and Z isomers of the conjugate addition products ofFormulas 8.3 and 8.4, as shown in step a. Subjecting the olefiniccompounds of Formulas 8.3 and 8.4 to the catalytic hydrogenationconditions previously disclosed in step b of Schemes 3, as shown in stepb, affords the alkoxy-ketones of Formulas 8.5 and 8.6, wherein R₁, R₂and R₅ are previously defined within the scope of this application.Subsequent reduction of the ketones may be accomplished throughtreatment of the compounds of Formulas 8.5 or 8.6 in an alcohol, such asMeOH with a reducing agent, such as sodium borohydride (NaBH₄).Alkylation of the resulting diastereomeric mixtures of the hydroxylintermediates may be achieved by treating the alcohols with an aminebase, such as 1,8-Bis(dimethylamino)naphthalene (Proton Sponge®), in asolvent such as CH₂Cl₂, followed by an alkylating agent, for exampletrimethyloxonium tetrafluoroborate, to give compounds of Formulas 8.7and 8.8, as shown in step c of Scheme 8.

Deprotection and Amide Formation

Picolinamide compounds of Formula 9.3, wherein R₁, R₂, X, and Y arepreviously defined herein, may be prepared as illustrated in steps a andb of Scheme 9. Amine salts of Formula 9.2, may be prepared by treating asolution of a bis-carbamate protected amine of Formula 9.1, wherein R5is tert-butoxy and R₁ and R₂ are previously defined within the scope ofthis disclosure, in a halogenated solvent, such as CH₂Cl₂ or chloroform(CHCl₃), or neat, with a solution of a mineral acid, for examplehydrogen chloride (HCl) in a solvent such as dioxane, to give the HClsalts of compounds of Formula 9.2, as shown in step a. In step b,solutions of compounds of Formula 9.2, wherein R₁ and R₂ are previouslydefined, are treated with 3-methoxy-4-hydroxypicolinic acid and anexcess of an organic base, such as diisopropylethyl amine orN-methylmorpholine, followed by a peptide coupling reagent, for examplebenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PyBOP) or(dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminiumhexafluorophosphate (HATU), in a halogenated solvent such as CH₂Cl₂ togive compounds of Formula 9.3, wherein X is hydrogen, Y is Q, and R₁ andR₂ are as defined within the scope of this disclosure.

Hydroxypyridine Substitution

Picolinamide compounds of Formula 10.2, wherein R₁, R₂, and R₃ arepreviously defined herein, may be prepared as illustrated in methods aorb of Scheme 10. Treating picolinamide compounds of Formula 10.1,wherein R₃ is hydrogen and R₁ and R₂ are previously defined, with anorganic base such as TEA and a catalyst, such as DMAP, in a halogenatedsolvent like CH₂Cl₂, followed by an acid chloride, for example acetylchloride or 3-methoxypropanoyl chloride, affords compounds of Formula10.2, as shown in method a. Alternatively, method b illustrates thattreating picolinamide compounds of Formula 10.1, wherein R₃ is hydrogenand R₁ and R₂ are previously defined, with a carbonate base, such assodium or potassium carbonate (Na₂CO₃ or K₂CO₃), with or without theaddition of a catalytic amount of sodium iodide (NaI) in a solvent likeacetone, followed by an alkyl halide, such as bromomethylacetate,chloromethylisobutyrate, or chloromethyl 2-ethoxyacetate (as prepared inMeyer, K. G.; Bravo-Altamirano, K.; Renga, J. M.; Herrick, J.; Nugent,B. M.; Boebel, T. A.; Li, F.; Wang, N. X.; Owen, W. J.; Graupner, P. R.;Yao, C.; Heemstra, R. J. Preparation of N-macrocyclyl picolinamides asfungicides. US 20130296375, Nov. 7, 2013) also affords picolinamidecompounds of Formula 10.2, wherein R₁, R₂, and R₃ are previously definedwithin the scope of this disclosure.

Acetal Formation

Acetal compounds of Formula 11.0, wherein R₅ is previously definedwithin the scope of this disclosure and R₁ is aryl, alkyl or alkenyl,may be prepared as shown in Scheme 11. In Scheme 11, treatment of abis-carbamate protected amine of Formula 1.11, such as the bistert-butylcarbamate, wherein R₁ and R₂ are hydrogen and R₅ istert-butoxy, with an aldehyde, such as benzaldehyde, in the present ofan acid catalyst, for example p-toluenesulfonic acid, and a dessicant,such as magnesium sulfate (MgSO₄), in a solvent such as CH₂Cl1₂ ortoluene at ambient temperature, affords the acetal product of Formula11.0, where and R₁ and R₅ are as defined above.

Aryl Functionalization

Functionalized compounds of Formula 12.2, wherein R₁ is aryl, R₂ isalkyl, and R₅ is as previously defined within the scope of thisdisclosure, and compounds of Formula 12.5, wherein R₁ is alkyl, R₂ isaryl, and R₅ is as previously defined within the scope of thisdisclosure, may be prepared as illustrated in Scheme 12, steps a and b.In step a, treatment of the aryl ethers of Formulas 12.0 and 12.3,wherein R₁, R₂, and R₅ are as defined above, with a halogenating agent,such as N-bromosuccinimide (NBS), in an aprotic solvent such as CH₂Cl₂at ambient temperature affords the halogenated compounds of Formulas12.1 and 12.4, wherein R₁, R₂, and R₅ are as defined above. In step b,the halogenated aryl ethers of Formulas 12.1 and 12.4, wherein R₁, R₂,and R₅ are as defined above, may be cross-coupled with a boronic acid orboronate ester, such as phenyl boronic acid, in the presence of a base,such as Na₂CO₃ and a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0) (Pd(PPh₃)₄), in a mixed solventsystem, for example dioxane/ water, at an elevated temperature, such as80° C., to give compounds of Formulas12.2 and 12.5, wherein R₁, R₂, andR₅ are as defined above and R₄ is alkyl, aryl, or alkenyl.

The following examples are presented to illustrate the various aspectsof the compounds of the present disclosure and should not be construedas limitations to the claims.

EXAMPLES Example 1

Preparation of (2S,3R,4S)-2-methyl-3,4-dihydro-2H-pyran-3,4-diol (C1)

To a solution of (2S,3S,4S)-2-methyl-3,4-dihydro-2H-pyran-3,4-diyldiacetate (32.10 grams (g), 150 millimole (mmol)) in MeOH (150milliliters (mL)) was added K₂CO₃ (2.07 g, 15.0 mmol). This mixture wasstirred for 16 h at 20° C. The resulting yellow solution was filteredthrough a plug of silica gel, 6 centimeters (cm)×2 cm, that was flushedwith EtOAc (500 mL). The solvent was concentrated to provide(2S,3R,4S)-2-methyl-3,4-dihydro-2H-pyran-3,4-diol (19.9 g, 102% yieldwith 95% purity resulting in 97% corrected yield) as a yellow solid,which was used without further purification:¹H NMR (400 MHz, CDCl₃) δ6.31 (dd, J=6.0, 1.6 Hz, 1 H), 4.70 (dd, J=6.0, 2.1 Hz, 1 H), 4.21 (dt,J =7.4, 1.9 Hz, 1 H), 3.85 (dq, J =9.9, 6.3 Hz, 1 H), 3.41 (dd, J =9.9,7.4 Hz, 1 H), 1.38 (d, J=6.3 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 144.82,102.65, 75.64, 74.36, 70.34, 17.09; EIMS m/z 130 ([M⁺]).

Example 2

Preparation of(2S,3S,4S)-3,4-bis(benzyloxy)-2-methyl-3,4-dihydro-2H-pyran (C2)

Sodium hydride, 60% dispersion in mineral oil, (NaH; 14.68 g, 367 mmol)was added to a 1 liter (L), 3-neck round bottomed flask under nitrogen.The NaH dispersion was washed with hexanes (100 mL and 50 mL) and thensuspended in anhydrous N,N-dimethylformamide (DMF; 230 mL) and cooled to0° C. in an ice water bath. The flask was fitted with a 125 mL additionfunnel that was then charged with(2S,3R,4S)-2-methyl-3,4-dihydro-2H-pyran-3,4-diol (19.9 g, 153 mmol) asa solution in anhydrous DMF (70 mL). The diol solution was added to theNaH suspension dropwise with modification of the flow rate to mitigatethe reaction rate and frothing. The addition took a total of 15 minutes(min). This mixture was then stirred at 0° C. for a further 30 min. Theaddition funnel was charged with benzyl bromide (40.0 ml, 336 mmol) thatwas added dropwise over 10 min. The mixture was then allowed to slowlywarm to 20° C. over 16 h. The reaction was quenched by the slow andcareful dropwise addition of saturated aqueous ammonium chloride (NH₄Cl)solution (20 mL), poured into methyl-t-butyl ether (MTBE; 900 mL),washed with water (600 mL) and saturated aqueous sodium chloride (NaCl,brine) solution (300 mL), dried over MgSO₄, filtered, and concentratedto provide a yellow oil (49.32 g, 99%; adjusted for 22 mo l% residualDMF): IR (thin film) 3063, 3030, 2975, 2870, 1645, 1496, 1453, 1236,1099, 1054, 733, 695 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.54−7.26 (m, 10H), 6.36 (dd, J=6.1, 1.1 Hz, 1 H), 4.95−4.80 (m, 2 H), 4.80−4.62 (m, 2H), 4.57 (d, J=11.7 Hz, 1 H), 4.21 (dt, J=6.5, 1.9 Hz, 1 H), 3.95 (dq,J=8.9, 6.4 Hz, 1 H), 3.49 (dd, J=8.9, 6.5 Hz, 1 H), 1.38 (d, J=6.4 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ144.82, 138.44, 138.29, 128.45, 128.00,127.79, 127.67, 100.17, 79.55, 74.11, 74.00, 70.58, 17.54.

Example 3

Preparation of(3R,4S,5S)-3,4-bis(benzyloxy)-5-methyltetrahydrofuran-2-ol (C3)

To a solution of (2S,3S,4S)-3,4-bis(benzyloxy)-2-methyl-3,4-dihydro-2H-pyran (41.8 g, 135 mmol) in CH₂Cl₂ (405 mL) and MeOH (50 mL) was addedNaHCO₃ (1.13 g, 13.5 mmol). This mixture was cooled to −78° C. (dryice/acetone bath) and a stream of ozone was passed through the reactionuntil the solution took on a blue color (2 h). Oxygen was passed throughuntil the blue color disappeared (10 min) and then dimethyl sulfide(19.9 ml, 269 mmol) was added. The solution was warmed to 20° C. andstirred overnight. The reaction was filtered through a plug of Celite®and concentrated to provide an oil. This oil was dissolved in THF (300mL), a solution of LiOH (9.68 g, 404 mmol) in water (150 mL) was added,and the mixture was stirred vigorously at 20° C. for 2.5 h. The phaseswere separated and the aqueous phase was extracted with EtOAc (2×100mL). The combined organic extracts were washed with saturated aqueousNaCl solution (100 mL), dried over MgSO₄, filtered, and concentrated toprovide a yellow oil. Purification by automated silica gel columnchromatography (5→30% acetone/hexanes) provided(3R,4S,5S)-3,4-bis(benzyloxy)-5-methyltetrahydrofuran-2-ol (34.1 g, 80%)as a yellow oil. The product exists as an inseparable mixture ofisomers: IR (neat film) 3402, 3031, 2934, 1658, 1496, 1454, 1367, 1105,1059, 989, 736, 697 cm⁻¹, ¹H NMR (400 MHz, CDCl₃) δ 7.45−7.25 (m, 42 H),5.37 (d, J=6.7 Hz, 3 H), 5.30 (dd, J=8.5, 4.3 Hz, 1 H), 4.66 (dd, J=5.3,2.4 Hz, 1 H), 4.6−4.47 (m, 16 H), 4.35 (qd, J=6.4, 4.9 Hz, 3 H), 3.98(dd, J=2.5, 0.9 Hz, 3 H), 3.97−3.89 (m, 2 H), 3.80 (d, J=8.5 Hz, 1 H),3.77−3.72 (m, 1H), 3.66 (ddd, J=4.8, 2.5, 0.7 Hz, 3H), 3.40 (d, J=6.7Hz, 3H), 1.34 (d, J=6.4 Hz, 3 H), 1.31 (d, J=6.4 Hz, 9 H); ¹³C NMR (101MHz, CDCl₃) δ137.73, 137.48, 137.42, 137.05, 128.63, 128.57, 128.52,128.50, 128.24, 128.08, 127.98, 127.94, 127.91, 127.82, 127.81, 127.69,127.00, 100.88, 95.90, 87.42, 87.31, 86.68, 83.14, 78.65, 76.43, 72.67,72.19, 71.97, 65.37, 20.84, 19.38.

Example 4 Preparation of (2S,3S,4S)-3,4-bis(benzyloxy)hex-5-en-2-ol (C4)

To a suspension of methyltriphenylphosphonium bromide (75.0 g, 211 mmol)in anhydrous THF (400 ml) under nitrogen at 0° C. (ice water bath) in a1000 mL, 3-neck round bottom flask was added a 2.5 molar (M) solution ofn-butyllithium in hexane (n-BuLi; 81.0 ml, 202 mmol) dropwise viasyringe, keeping the internal temperature below 15° C. The resulting redsolution was stirred at 0° C. for 45 min and then cooled to −78° C. (dryice/acetone bath). A solution of(3R,4S,5S)-3,4-bis(benzyloxy)-5-methyltetrahydrofuran-2-ol (26.5 g, 84mmol) in anhydrous THF (20 mL) was added via syringe and the solutionwas stirred for 30 min at −78 ° C., and then removed from the cold bathand stirred at 20° C. for 16 h. The reaction was quenched with saturatedaqueous NH₄Cl solution (200 mL), diluted with water (200 mL) and diethylether (Et₂O; 400 mL). The and the aqueous phase was extracted with Et₂O(2×200 mL). The combined organic phases were dried over MgSO₄, filtered,and concentrated to provide an orange oil. Purification by automatedsilica gel column chromatography (2420% acetone/hexanes) provided(2S,3S,4S)-3,4-bis(benzyloxy)hex-5-en-2-ol (20.23 g, 77%) as a yellowoil: ¹H NMR (400 MHz, CDCl₃) δ7.45=7.25 (m, 10 H), 5.92 (ddd, J=17.2,10.6, 7.6 Hz, 1 H), 5.44−5.25 (m, 2 H), 4.75 (d, J=11.6 Hz, 1 H),4.70−4.54 (m, 2 H), 4.38 (d, J=11.8 Hz, 1 H), 4.12−3.99 (m, 1 H), 3.91(h, J=6.3 Hz, 1 H), 3.50−3.35 (m, 1 H), 2.73 (d, J =5.9 Hz, 1 H), 1.17(d, J=6.3 Hz, 3 H); ¹³C NMR (101 MHz, CDCl₃) δ138.31, 137.79, 134.47,128.46, 128.37, 127.95, 127.94, 127.79, 127.72, 119.27, 83.70, 81.18,74.07, 70.61, 67.37, 18.90; ESIMS m/z 313.5 ([M+Na]⁺).

Example 5

Preparation of (2S,3S,4S)-3,4-bis(benzyloxy)hex-5-en-2-yl acetate (C5)

To a solution of (2S,3S,4S)-3,4-bis(benzyloxy)hex-5-en-2-ol (800milligrams (mg), 2.56 mmol) in CH₂Cl₂ (10 mL) at room temperature wasadded TEA (1.07 ml, 7.68 mmol), acetic anhydride (0.48 ml, 5.12 mmol)and DMAP (62.6 mg, 0.512 mmol). The reaction mixture was stirred at roomtemperature for 2 h, concentrated and purified by column chromatographyon SiO₂ (0→20% EtOAc/hexanes) to yield the title compound as a colorlessoil (891 mg, 98%): ¹H NMR (400 MHz, CDCl₃) δ7.41−7.23 (m, 10 H), 5.84(ddd, J=17.2, 10.4, 8.2 Hz, 1 H), 5.38−5.26 (m, 2 H), 5.02 (qd, J=6.5,3.7 Hz, 1 H), 4.83−4.67 (m, 2 H), 4.61 (d, J=11.8 Hz, 1 H), 4.37 (d,J=11.8 Hz, 1 H), 3.84 (ddt, J=8.0, 6.3, 0.8 Hz, 1 H), 3.63 (dd, J=6.3,3.7 Hz, 1H), 1.91 (s, 3H), 1.26 (d, J=6.5 Hz, 3 H); ¹³C NMR (101 MHz,CDCl₃) δ170.19, 138.64, 138.30, 135.07, 128.33, 128.25, 128.08, 127.94,127.58, 127.52, 119.42, 82.90, 81.86, 74.98, 71.03, 70.48, 21.32, 14.75;ESIMS m/z 377.3 ([M+Na]⁺).

Example 6

Preparation of (6S,7S,8S,Z)-methyl8-acetoxy-6,7-bis(benzyloxy)-2-((tert-butoxycarbonyl)amino)non-2-enoate(C6)

To a solution of (2S,3S,4S)-3,4-bis(benzyloxy)oct-7-en-2-yl acetate (931mg, 2.63 mmol) in THF (2 mL) was added 9-BBN (0.5 M solution in THF,6.82 mL, 3.41 mmol). The reaction mixture was stirred at roomtemperature for 30 min, then warmed to 50° C. and stirred for 2 h. Afterthe reaction mixture was cooled to room temperature, an aqueous solutionof potassium phosphate (K₃PO₄; 3 M, 1.75 mL, 5.25 mmol), a solution of(Z)-methyl 3-bromo-2-((tert-butoxycarbonyl)amino)acrylate (736 mg, 2.63mmol) in DMF (9 mL, degassed), and PdCl₂(dppf) (96 mg, 0.13 mmol) wasadded. The reaction mixture was heated to 55° C. and stirred overnight,and then quenched with saturated aqueous NaHCO₃ and extracted with Et₂O.The combined organic phase was dried over sodium sulfate (Na₂SO₄),filtered, concentrated, and purified by column chromatography on SiO₂(0430% EtOAc/hexanes) to yield the title compound as a light yellow oil(1.26 g, 86%): IR (thin film) 3341, 2930, 1717, 1367, 1241 cm⁻¹; ¹H NMR(400 MHz, CDCl₃) δ7.43−7.26 (m, 10 H), 6.48 (t, J=7.3 Hz, 1 H), 6.03 (s,1 H), 5.08 (qd, J=6.5, 3.1 Hz, 1 H), 4.77−4.58 (m, 3 H), 4.49 (d, J=11.2Hz, 1 H), 3.76 (s, 3 H), 3.64 (dd, J=6.1, 3.1 Hz, 1 H), 3.44 (ddd,J=7.9, 6.0, 4.2 Hz, 1 H), 2.43−2.29 (m, 1 H), 2.29−2.16 (m, 1 H), 1.98(s, 3 H), 1.85−1.61 (m, 2 H), 1.44 (s, 9 H), 1.31 (d, J=6.5 Hz, 3 H);¹³C NMR (101 MHz, CDCl₃) δ170.32, 165.29, 153.24, 138.41, 138.31,135.67, 128.33, 128.04, 127.98, 127.68, 127.62, 81.82, 80.45, 79.30,74.33, 73.15, 71.22, 70.56, 52.29, 29.54, 28.18, 24.66, 21.32, 15.09;HRMS—ESI (m/z) [M+H]⁺ calcd for C₃₁H₄₂NO₈, 556.2905; found, 556.2903.

Example 7

Preparation of(2S,6S,7S,8S)-methyl-8-acetoxy-6,7-bis(benzyloxy)-2-((tert-butoxycarbonyl)amino)nonanoate(C7)

A solution of (6S,7S,8S,Z)-methyl8-acetoxy-6,7-bis(benzyloxy)-2-((tert-butoxycarbonyl)amino)non-2-enoate(120 mg, 0.216 mmol) in anhydrous MeOH (4.3 mL) was purged with N₂ for15 min in a 250 mL stainless steel bomb. To the solution was added1,2-bis[(2S,5S)-2,5-diethyl-phospholano]benzene(1,5-cyclooctadiene)rhodium(I)trifluoromethanesulfonate ((S,S)-Et-DUPHOS-Rh; 1.56 mg, 2.16 micromole(μmol)), and the vessel was sealed, purged twice with hydrogen (H₂; 200psi), and then pressurized to 200 psi with H₂ and stirred at roomtemperature overnight. The reaction was concentrated and purified bycolumn chromatography on SiO₂ (0→30% EtOAc/hexanes) to yield the titlecompound as a colorless oil (110 mg, 91%): ¹HNMR (400 MHz, CDCl₃)δ7.39−7.23 (m, 10 H), 5.10−5.04 (m, 1 H), 4.97 (d, J=8.4 Hz, 1 H), 4.73(d, J=11.6 Hz, 1 H), 4.65 (d, J=7.7 Hz, 1 H), 4.62 (d, J=7.4 Hz, 1 H),4.50 (d, J =11.4 Hz, 1 H), 4.32−4.20 (m, 1 H), 3.70 (s, 3 H), 3.61 (dd,J=6.0, 3.1 Hz, 1 H), 3.43−3.39 (m, 1 H), 1.98 (s, 3 H), 1.79−1.66 (m,1H), 1.64 - 1.47 (m, 4H), 1.45 (s, 9H), 1.31 (d, J=6.5 Hz, 3 H),1.29−1.20 (m, 1 H); ¹³C NMR (101 MHz, CDCl₃) δ173.27, 170.24, 155.35,138.51, 138.45, 128.33, 128.05, 128.01, 127.67, 127.63, 81.89, 79.82,79.39, 74.30, 73.07, 71.28, 53.33, 52.21, 32.68, 30.52, 28.34, 21.34,15.13; ESIMS m/z 580.4 ([M+Na]⁺).

Example 8

Preparation of(2S,6S,7S,8S)-6,7-bis(benzyloxy)-2-((tert-butoxycarbonyl)amino)-8-hydroxynonanoicacid (C8)

To a solution of (2S,6S,7S,8S)-methyl8-acetoxy-6,7-bis(benzyloxy)-2-((tert-butoxycarbonyl)amino)nonanoate(110 mg, 0.20 mmol) in MeOH (2 mL) and water (2 mL) at room temperaturewas added LiOH·H₂O (33.1 mg, 0.789 mmol). The reaction mixture wasstirred at room temperature for 3 h, quenched with 1 Normal (N)hydrochloric acid, and extracted with EtOAc. The combined organic phaseswere washed with saturated aqueous NaHCO₃, dried over Na₂SO₄, filtered,and concentrated to yield the title compound as a colorless oil (96 mg,97%): IR (thin film) 3409, 2929, 1686, 1588; ¹H NMR (400 MHz, CDCl₃) δ7.33−7.21 (m, 10 H), 5.40 (s, 1 H), 4.56−4.48 (m, 4 H), 3.96−3.81 (m, 2H), 3.57−3.51 (m, 1 H), 3.31−3.23 (m, 1 H), 1.81−1.41 (m, 6 H), 1.37 (s,9 H), 1.19 (d, J=6.2 Hz, 3H); ESIMS m/z 524.4 ([M+Na]⁺).

Example 9

Preparation of tert-butyl((3S,7S,8S,9S)-7,8-bis(benzyloxy)-9-methyl-2-oxooxonan-3-yl)carbamate(C9)

To a solution of DMAP (137 mg, 1.12 mmol) and MNBA (129 mg, 0.375 mmol)in CH₂Cl₂ (30 mL) at room temperature was added a solution of(2S,6S,7S,8S)-6,7-bis(benzyloxy)-2-((tert-butoxycarbonyl)amino)-8-hydroxynonanoicacid (94 mg, 0.19 mmol) in CH₂Cl₂ (8 mL) over 4 h via syringe pump. Thereaction mixture was stirred overnight, concentrated and purified bycolumn chromatography on SiO₂ (0→20%, EtOAc/hexanes) to yield the titlecompound as a colorless oil (71 mg, 78%): ¹H NMR (400 MHz, CDCl₃) δ7.41−7.26 (m, 10 H), 5.03 (d, J=8.3 Hz, 1 H), 4.88 (d, J=10.8 Hz, 1 H),4.85−4.77 (m, 1 H), 4.68 (d, J=10.8 Hz, 1 H), 4.61 (d, J=11.4 Hz, 1 H),4.48 (d, J=11.4 Hz, 1 H), 4.20 (dt, J=10.9, 7.7 Hz, 1 H), 3.67−3.57 (m,2 H), 2.26 (dt, J=13.6, 6.7 Hz, 1 H), 2.21−2.09 (m, 1 H), 1.77−1.60 (m,2 H), 1.44 (s, 9 H), 1.41 (d, J=6.4 Hz, 3 H), 1.23−1.11 (m, 1 H),0.99−0.87 (m, 1 H); ¹³C NMR (101 MHz, CDCl₃) δ 173.15, 154.91, 138.40,138.31, 128.39, 128.37, 127.94, 127.80, 127.71, 127.64, 83.90, 83.70,79.91, 75.77, 72.76, 71.20, 52.76, 33.88, 28.32, 28.00, 18.28, 18.10;ESIMS m/z 506.3([M+Na]⁺).

Example 10

Preparation of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-7,8-dibenzyloxy-9-methyl-2-oxo-oxonan-3-yl]carbamate(C10)

A solution of tert-butyl((3S,7S,8S,9S)-7,8-bis(benzyloxy)-9-methyl-2-oxooxonan-3-yl)carbamate(150 mg, 0.31 mmol), DMAP(19.0 mg, 0.155 mmol) and di-tert-butyldicarbonate (271 mg, 1.24 mmol) in CH₃CN (2.1 mL) was stirred at roomtemperature for 18 h, concentrated, and purified by columnchromatography on SiO₂ (0→15% EtOAc/hexanes) to yield the title compound(76 mg, 42%) as a colorless oil along with recovered starting material(72 mg, 48%) as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 7.35−7.27 (m,10 H), 4.88 (d, J=10.9 Hz, 1 H), 4.83 (dd, J=10.4, 8.0 Hz, 1 H),4.75−4.59 (m, 3 H), 4.49 (d, J=11.4 Hz, 1 H), 3.69−3.57 (m, 2 H),2.42−2.33 (m, 1 H), 2.24−2.14 (m, 1 H), 2.08−2.00 (m, 1 H), 1.79−1.65(m, 2H), 1.51 (s, 18H), 1.41 (d, J=6.3 Hz, 3H), 1.01 (ddt, J=16.0, 7.7,1.8 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 170.86, 152.91, 138.52, 138.41,128.39, 128.36, 127.95, 127.83, 127.68, 127.60, 84.08, 83.59, 82.71,75.65, 72.95, 71.21, 57.43, 30.55, 28.50, 27.99, 19.28, 18.23; ESIMS m/z606.4 ([M+Na]⁺).

Example 11

Preparation of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8R,9S)-7,8-dihydroxy-9-methyl-2-oxo-oxonan-3-yl]carbamate(F1)

A mixture of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-7,8-dibenzyloxy-9-methyl-2-oxo-oxonan-3-yl]carbamate(66.0 mg, 0.113 mmol) and Pd/C (5% w/w Pd, 24.1 mg, 0.011 mmol) in EtOAc(2.3 mL) was stirred under an H₂ balloon at room temperature for 7 h.The reaction mixture was filtered through Celite® , and concentrated toyield the title compound (44.0 mg, 96%) as a colorless oil: ¹H NMR (400MHz, CDCl₃) δ 4.83 (dd, J=10.1, 7.3 Hz, 1 H), 4.72 (dq, J=9.1, 6.3 Hz, 1H), 3.58−3.42 (m, 2 H), 2.84 (s, 1 H), 2.45 (s, 1 H), 2.35 (dtd, J=13.8,9.8, 2.2 Hz, 1 H), 2.14−2.02 (m, 1 H), 1.96−1.67 (m, 3 H), 1.51 (s, 18H), 1.42 (d, J=6.3 Hz, 3 H), 1.31−1.21 (m, 1 H); ¹³C NMR (101 MHz,CDCl₃) δ 170.77, 152.91, 82.81, 76.85, 73.86, 73.18, 57.69, 35.34,30.93, 27.98, 20.03, 18.06; ESIMS m/z 426.3 ([M+Na]⁺).

Example 12

Preparation of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8R,9S)-7-hydroxy-9-methyl-2-oxo-8-phenoxy-oxonan-3-yl]carbamate(C11)

A solution of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8R,9S)-7,8-dihydroxy-9-methyl-2-oxo-oxonan-3-yl]carbamate(1.845 g, 4.57 mmol), triphenylbismuth diacetate (3.06 g, 5.49 mmol) anddiacetoxycopper (0.166 g, 0.915 mmol) in toluene (18.3 ml) was stirredat 40° C. for 1 h. The reaction mixture was filtered thru Celite® , thepad washed with toluene (2×40 mL), and the filtrate concentrated toyield 2.3 g light blue foam. Purification by column chromatography(SiO₂, 0→20% EtOAc/hexanes) yielded the title compound as a white foam(1.15 g, 52%), along with the 7-substituted and 7,8-disubstitutedproducts: ¹H NMR (400 MHz, CDCl₃) δ 7.33−7.24 (m, 2 H), 7.03 (d, J=7.9Hz, 2 H), 6.98 (t, J=7.3 Hz, 1 H), 4.96−4.80 (m, 2 H), 4.29 (dd, J=9.4,7.9 Hz, 1 H), 3.86 (t, J=6.7 Hz, 1 H), 2.47−2.27 (m, 2 H), 2.15−1.95 (m,2 H), 1.91−1.71 (m, 2 H), 1.59−1.40 (m, 19 H), 1.31 (d, J=6.4 Hz, 3 H);¹³C NMR (101 MHz, CDCl₃) δ 170.73, 159.42, 152.85, 129.69, 121.92,116.27, 83.73, 82.78, 73.98, 72.46, 57.56, 33.41, 30.90, 27.98, 19.79,18.31; HRMS-ESI (m/z) [M+Na]⁺calcd for C₂₅H₃₇NNaO₈, 502.2411; found,502.2344.

The following compounds were prepared and isolated using theappropriately substituted triphenylbismuth diacetate reagents and themethodology described in Example 12:tert-ButylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-8-hydroxy-9-methyl-2-oxo-7-phenoxy-oxonan-3-yl]carbamate(C12)

Isolated as a white foam (520 mg, 24%): ¹H NMR (400 MHz, CDCl₃) δ7.35−7.27 (m, 2 H), 7.03−6.95 (m, 1 H), 6.92 (dd, J=8.7, 1.0 Hz, 2 H),4.95 (t, J=8.5 Hz, 1 H), 4.84 (dq, J=9.6, 6.3 Hz, 1 H), 4.24−4.12 (m, 1H), 3.86 (ddd, J=9.9, 7.8, 2.4 Hz, 1 H), 2.63 (d, J=2.5 Hz, 1 H),2.38−2.20 (m, 1 H), 2.13−1.98 (m, 2 H), 1.89 (tt, J=11.1, 5.6 Hz, 1 H),1.65−1.54 (m, 2 H), 1.51 (s, 18 H), 1.47 (d, J=6.3 Hz, 3 H); ¹³C NMR(101 MHz, CDCl₃) δ 170.56, 157.12, 152.90, 129.63, 121.65, 116.60,82.78, 82.32, 75.72, 72.93, 57.26, 31.06, 30.37, 27.98, 20.17, 18.19;HRMS-ESI (m/z) [M+Na]⁺calcd for C₂₅H₃₇NNa0₈, 502.2411; found, 502.2399.

tert-ButylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-9-methyl-2-oxo-7,8-diphenoxy-oxonan-3-yl]carbamate(C13)

Isolated as a white solid (172 mg, 7%): ¹H NMR (400 MHz, CDCl₃) δ7.30−7.14 (m, 4 H), 7.04 (dd, J=8.8, 1.0 Hz, 2 H), 6.97−6.86 (m, 2 H),6.86−6.77 (m, 2 H), 4.98 (dd, J=9.5, 6.4 Hz, 1 H), 4.91 (dd, J=10.0, 8.3Hz, 1 H), 4.62 (dd, J=9.5, 7.4 Hz, 1 H), 4.52 (ddd, J=7.1, 5.2, 1.6 Hz,1 H), 2.46−2.18 (m, 2 H), 2.08 (dd, J=13.5, 6.8 Hz, 1 H), 1.91 (dt,J=13.0, 7.3 Hz, 1 H), 1.72 (m, H), 1.52 (s, 18 H), 1.41 (d, J=6.4 Hz, 3H), 1.20 (dt, J=7.7, 1.8 Hz, 1 H); ¹³C NMR (101 MHz, CDCl₃) δ 170.71,159.55, 157.64, 152.85, 129.39, 129.37, 121.54, 121.35, 116.72, 116.57,82.81, 82.37, 82.21, 72.57, 57.25, 30.54, 28.98, 27.99, 19.32, 18.32;ESIMS m/z 578.8 ([M+Na]⁺).

tert-ButylN-tert-butoxycarbonyl-N-[(3S,7S,8R,9S)-8-(4-fluorophenoxy)-7-hydroxy-9-methyl-2-oxo-oxonan-3-yl]carbamate(C14)

Isolated as a colorless oil (150 mg, 0.30 mmol, 61%): ¹H NMR (400 MHz,CDCl₃) δ 7.04−6.90 (m, 4 H), 4.93−4.82 (m, 2 H), 4.17 (dd, J=9.4, 7.9Hz, 1 H), 3.86 (ddd, J=8.1, 6.1, 2.4 Hz, 1 H), 2.40 (dtd, J=13.7, 9.9,3.5 Hz, 2 H), 2.16−1.94 (m, 2 H), 1.82 (dd, J=6.1, 3.1 Hz, 2 H), 1.52(s, 18 H), 1.49−1.41 (m, 1 H), 1.31 (d, J=6.4 Hz, 3 H); ¹³C NMR (101MHz, CDCl₃)δ 170.69 , 157.76 (d, J=240.0 Hz), 155.62 (d, J=2.3 Hz),152.85, 117.54 (d, J=8.0 Hz), 116.04 (d, J=23.2 Hz), 84.90 , 82.82 ,73.96 , 72.30 , 57.53 , 33.52 , 30.86 , 27.97 , 19.78 , 18.35; ESIMS m/z498.3 [(M+H)⁺].

Example 12A

Preparation of[(3S,7S,8S,9S)-9-methyl-2-oxo-7,8-diphenoxy-oxonan-3-yl]ammoniumchloride (F2)

A solution of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-9-methyl-2-oxo-7,8-diphenoxy-oxonan-3-yl]carbamate(650 mg, 1.17 mmol) and HCl (4 M in dioxane; 5.85 mL, 23.4 mmol) inCHCl₃ (6 mL) was stirred at 23° C. for 1.5 h. The solution wasconcentrated to yield the title compound as a white foam (458 mg, 100%),which was used without further purification.

Example 12B

Step 1: Preparation of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-9-methyl-7-(2-methylallyloxy)-2-oxo-8-phenoxy-oxonan-3-yl]carbamate(C15)

A solution of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8R,9S)-7-hydroxy-9-methyl-2-oxo-8-phenoxy-oxonan-3-yl]carbamate(1.075 g, 2.24 mmol), tert-butyl (2-methylallyl) carbonate (1.158 g,6.70 mmol), dppf (0.025 g, 0.045 mmol) and Pd₂(dba)₃ (0.021 g, 0.022mmol) in degassed THF (11.2 ml) was heated to 60° C. for 1.5 h. Thesolution was cooled to room temperature and purified by columnchromatography (SiO₂; 0→5% EtOAc/Hex) to yield the title compound (1.0g, 84%) as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 7.34−7.17 (m, 2 H),7.09−7.02 (m, 2 H), 6.98−6.90 (m, 1 H), 4.94−4.72 (m, 4 H), 4.43 (dd,J=9.6, 7.4 Hz, 1 H), 3.91 (d, 1 H), 3.79 (d, 1 H), 3.62 (ddd, J=7.0,5.1, 1.7 Hz, 1 H), 2.47−2.34 (m, 1 H), 2.25−2.13 (m, 1 H), 2.11−2.01 (m,1 H), 1.88−1.63 (m, 2 H), 1.56 (s, 3 H), 1.52 (s, 18 H), 1.33 (d, J=6.4Hz, 3H), 1.07 (dd, J =16.0, 7.7 Hz, 1 H); ¹³C NMR (101 MHz, CDCl₃) δ170.80, 159.58, 152.86, 142.36, 129.36, 121.24, 116.29, 112.34, 82.72,82.53, 82.06, 73.50, 72.76, 57.39, 30.56, 28.61, 27.98, 19.40, 19.29,18.19; HRMS-ESI (m/z) [M+Na]⁺calcd for C₂₉H₄₃NNaO₈, 556.2881; found,556.2873.

The following compounds were prepared and isolated using the methodologydescribed in Example 12B, Step 1:

tert-ButylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-9-methyl-8-(2-methylallyloxy)-2-oxo-7-phenoxy-oxonan-3-yl]carbamate(C16)

Isolated as a white solid (448 mg; 85%): ¹H NMR (400 MHz, CDCl₃) δ7.30−7.23 (m, 2 H), 6.99−6.88 (m, 3 H), 4.94−4.72 (m, 4 H), 4.46−4.35(m, 1 H), 4.22−4.16 (m, 1 H), 4.03 (d, J=11.6 Hz, 1 H), 3.67 (dd, J=9.7,7.1 Hz, 1 H), 2.38−2.25 (m, 1 H), 2.25−2.10 (m, 1 H), 2.04−1.95 (m, 1H), 1.83 (m 1 H), 1.65 (s, 3 H), 1.63−1.57 (m, 1 H), 1.49 (s, 18 H),1.46 (d, J=6.3 Hz, 3 H), 1.08 (dd, J=16.0, 7.8 Hz, 1 H); ¹³C NMR (101MHz, CDCl₃) δ170.75, 157.45, 152.86, 142.27, 129.49, 121.17, 116.55,112.39, 83.08, 83.01, 82.73, 77.41, 72.73, 57.27, 30.44, 28.80, 27.98,19.74, 19.18, 18.23; HRMS-ESI (m/z) [M+Na]⁺ calcd for C₂₉H₄₃NNaO₈,556.2881; found, 556.2875.

Example 12B

Step 2: Preparation of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-7-isobutoxy-9-methyl-2-oxo-8-phenoxy-oxonan-3-yl]carbamate(C17)

A suspension of Pd/C (5% w/w Pd; 199 mg) and tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-9-methyl-7-(2-methylallyloxy)-2-oxo-8-phenoxy-oxonan-3-yl]carbamate(1.00 g, 1.87 mmol) in EtOAc (9.4 mL) was stirred rapidly at roomtemperature under one atmosphere (atm) of H₂ overnight. The suspensionwas filtered through Celite®, washed with EtOAc (3×30 mL), and thecombined extracts were concentrated to yield the title compound as aclear oil (980 mg, 98%): ¹H NMR (400 MHz, CDCl₃) δ7.27−7.16 (m, 2 H),7.12−7.01 (m, 2 H), 6.99−6.86 (m, 1 H), 4.94−4.73 (m, 2 H), 4.38 (dd,J=9.6, 7.3 Hz, 1 H), 3.53 (ddd, J=7.1, 5.2, 1.7 Hz, 1 H), 3.24 (dd,J=8.8, 6.6 Hz, 1 H), 3.05 (dd, J=8.8, 6.3 Hz, 1 H), 2.53−2.29 (m, 1 H),2.29−2.11 (m, 1 H), 2.04 (s, 1 H), 1.88−1.60 (m, 3 H), 1.60−1.40 (m, 18H), 1.33 (d, J=6.4 Hz, 3 H), 1.05 (dd, J=16.0, 7.8 Hz, 1 H), 0.78 (d,J=6.7 Hz, 3 H), 0.73 (d, J=6.7 Hz, 3 H); ¹³C NMR (101 MHz, CDCl₃) δ170.84, 159.72, 152.86, 129.27, 121.17, 116.42, 83.13, 82.72, 82.70,76.40, 72.72, 57.41, 30.58, 28.70, 28.49, 27.98, 19.36, 19.24, 19.21,18.20; HRMS-ESI (m/z) [M+Na]⁺calcd for C₂₉H₄₅NNaO₈, 558.3037; found,558.3030.

The following compounds were prepared and isolated using the methodologydescribed in Example 12B, Step 2:

tert-ButylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-8-isobutoxy-9-methyl-2-oxo-7-phenoxy-oxonan-3-yl]carbamate(C18)

Isolated as a white solid (430 mg; 100%): ¹H NMR (400 MHz, CDCl₃) δ7.32−7.22 (m, 2 H), 6.99−6.86 (m, 3 H), 4.86 (dd, J=10.2, 8.2 Hz, 1 H),4.75 (dq, J=9.7, 6.3 Hz, 1 H), 4.43−4.26 (m, 1 H), 3.66−3.50 (m, 2 H),3.36 (dd, J=8.7, 6.7 Hz, 1 H), 2.44−2.24 (m, 1 H), 2.24−2.08 (m, 1H),2.04−1.91 (m, 1 H), 1.89−1.56 (m, 3 H), 1.53−1.46 (m, 18 H), 1.44 (d,J=6.3 Hz, 3H), 1.06 (dd, J=16.0, 7.9 Hz, 1H), 0.82 (d, J=6.7 Hz, 3H),0.78 (d, J=6.7 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 170.78, 157.65,152.86, 129.44, 121.06, 116.54, 83.33, 83.06, 82.71, 80.56, 72.93,57.27, 30.46, 28.97, 28.85, 27.97, 19.39, 19.28, 19.17, 18.15; HRMS-ESI(m/z) [M+Na]⁺ calcd for C₂₉H₄₅NNaO₈, 558.3037; found, 558.2994.

Example 12B

Step 3: Preparation of[(3S,7S,8S,9S)-7-isobutoxy-9-methyl-2-oxo-8-phenoxy-oxonan-3-yl]ammoniumchloride (F3)

Prepared according to the methods described in Example 12A.

The following compounds were prepared and isolated using the methodologydescribed in Example 12B, Step 3:

[(3S,7S,8S,9S)-8-Isobutoxy-9-methyl-2-oxo-7-phenoxy-oxonan-3-yl]ammoniumchloride (F4)

Example 12C

Step 1: Preparation of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,95)-8-(4-fluorophenoxy)-7-(4-methoxyphenoxy)-9-methyl-2-oxo-oxonan-3-yl]carbamate(C19)

To a stirred solution of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8R,9S)-8-(4-fluorophenoxy)-7-hydroxy-9-methyl-2-oxo-oxonan-3-yl]carbamate(150 mg, 0.30 mmol) in toluene (1.51 mL) under N₂ was addedtri(p-methoxyphenyl)bismuth diacetate (391 mg, 0.603 mmol) followed bydiacetoxycopper (10.9 mg, 0.060 mmol) andN-cyclohexyl-N-methylcyclohexanamine (129 microliters (μL), 0.603 mmol).The reaction mixture was heated for 18 h at 43° C. The reaction wasconcentrated and purified by column chromatography (04100% EtOAc/hex) toyield the title compound (75 mg, 41%) as a yellow oil: ¹ H NMR (400 MHz,CDCl₃) δ 7.07−6.97 (m, 2 H), 6.96−6.85 (m, 2 H), 6.81−6.69 (m, 4 H),4.99−4.85 (m, 2 H), 4.47 (dd, J=9.6, 7.4 Hz, 1 H), 4.34 (dt, J=5.5, 3.5Hz, 1 H), 3.73 (s, 3 H), 2.37 (q, J=10.7 Hz, 1 H), 2.22 (ddt, J=15.4,9.6, 5.2 Hz, 1 H), 2.12−1.98 (m, 1 H), 1.95−1.80 (m, 1 H), 1.73 (dd,J=14.5, 7.2 Hz, 1 H), 1.51 (s, 18 H), 1.40 (d, J=6.4 Hz, 3 H), 1.15 (dd,J=16.0, 7.7 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ−122.84; HRMS-ESI (m/z)[M+Na]⁺ calcd for C₃₂H₄₂FNNaO₉, 626.2736; found, 626.2739.

Example 12C

Step 2: Preparation of[(3S,7S,8S,9S)-8-(4-fluorophenoxy)-7-(4-methoxyphenoxy)-9-methyl-2-oxo-oxonan-3-yl]ammoniumchloride (F5)

Prepared according to the methods described in Example 12A.

Example 13

Preparation of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8R,9S)-7-hydroxy-9-methyl-8-(2-methylallyloxy)-2-oxo-oxonan-3-yl]carbamate(C20)

A solution of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8R,9S)-7,8-dihydroxy-9-methyl-2-oxo-oxonan-3-yl]carbamate(100 mg, 0.25 mmol), bis(2-methylallyl) carbonate (51 mg, 0.30 mmol),dppf (14 mg, 0.025 mmol) and Pd₂(dba)₃ (11.4 mg, 0.012 mmol) in degassedTHF (1.24 mL) was heated to 60° C. for 1.5 h. The solution was cooled toroom temperature and purified by column chromatography (SiO₂; 0→5%EtOAc/hexanes) to yield the title compound (61 mg, 54%) as a whitesolid: ¹H NMR (400 MHz, CDCl₃) δ 5.03−4.97 (m, 1 H), 4.90 (s, 1 H), 4.82(dd, J=10.4, 7.1 Hz, 1 H), 4.74 (dq, J=9.5, 6.3 Hz, 1 H), 4.09 (s, 2 H),3.64−3.56 (m, 1 H), 3.23 (dd, J=9.4, 7.7 Hz, 1 H), 2.53 (d, J=1.5 Hz, 1H), 2.43−2.30 (m, 1 H), 2.12−2.00 (m, 1 H), 1.92−1.80 (m, 1 H), 1.77 (m,5 H), 1.61−1.45 (m, 19 H), 1.42 (d, J=6.4 Hz, 3 H); ¹³C NMR (101 MHz,CDCl₃) δ 170.73, 152.84, 141.85, 112.38, 85.49, 82.70, 77.62, 73.37,72.70, 57.77, 34.76, 30.87, 27.96, 19.99, 19.67, 18.23; HRMS-ESI (m/z)[M+Na]⁺ calcd for C₂₃H₃₉NNaO₈, 480.2568; found, 480.2572.

The following compounds were prepared and isolated using theappropriately substituted allyl carbonate and the methodology describedin Example 13:tert-ButylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-8-hydroxy-9-methyl-7-(2-methylallyloxy)-2-oxo-oxonan-3-yl]carbamate(C21)

Isolated as a white solid (25 mg; 22%): ¹H NMR (400 MHz, CDCl₃) δ5.01−4.95 (m, 1 H), 4.91 (s, 1 H), 4.85 (dd, J=9.5, 7.6 Hz, 1 H),4.80−4.67 (m, 1 H), 4.01 (d, J=12.2 Hz, 1 H), 3.83 (d, J=12.2 Hz, 1 H),3.56 (ddd, J=9.5, 7.7, 2.0 Hz, 1 H), 3.21 (td, J=7.6, 2.1 Hz, 1 H), 2.85(d, J=2.0 Hz, 1 H), 2.40−2.23 (m, 1 H), 2.13−2.00 (m, 1 H), 1.93 (dt,J=14.0, 6.9 Hz, 1 H), 1.84−1.73 (m, 4 H), 1.70−1.56 (m, 1 H), 1.51 (s,18 H), 1.46−1.38 (m, 4 H); ¹³C NMR (101 MHz, CDCl₃) δ 170.74, 152.92,141.77, 112.89, 82.69, 81.96, 75.76, 73.49, 73.25, 57.61, 31.12, 31.04,27.98, 20.37, 19.67, 18.16; HRMS-ESI (m/z) [M+Na]⁺ calcd forC₂₃H₃₉NNaO₈, 480.2568; found, 480.2576.

tert-ButylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-9-methyl-7,8-bis(2-methylallyloxy)-2-oxo-oxonan-3-yl]carbamate(C22)

Isolated as a white solid (200 mg; 5%): ¹H NMR (400 MHz, CDCl₃) δ5.03−4.91 (m, 2 H), 4.90−4.75 (m, 3 H), 4.67 (dq, J=9.0, 6.3 Hz, 1 H),4.25 (d, J=11.7 Hz, 1 H), 3.99 (dd, J=21.0, 11.9 Hz, 2 H), 3.90−3.79 (m,1 H), 3.56−3.35 (m, 2 H), 2.44−2.27 (m, 1 H), 2.12 (ddd, J=23.7, 9.0,5.0 Hz, 1 H), 2.02 (dt, J=13.3, 6.5 Hz, 1 H), 1.74 (s, 3 H), 1.75 (s, 3H), 1.72−1.54 (m, 3 H), 1.51 (s, 18 H), 1.40 (d, J=6.3 Hz, 3 H),1.03−0.91 (m, 1 H); ¹³C NMR (101 MHz, CDCl₃) δ 170.86, 152.90, 142.54,142.48, 112.09, 111.94, 83.62, 82.67, 73.10, 72.99, 57.43, 30.55, 28.52,27.98, 19.80, 19.70, 19.24, 18.12; EIMS m/z 534.8 ([M+Na]⁺)

tert-ButylN-tert-butoxycarbonyl-N-[(3S,7S,8R,9S)-8-cyclopent-2-en-l-yloxy-7-hydroxy-9-methyl-2-oxo-oxonan-3-yl]carbamate(C23)

Isolated as a yellow foam (344 mg, 41%): IR (neat) 3520, 2978, 2928,1744, 1704, 1358 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.09−6.04 (m, 1 H),5.96 (dq, J=5.9, 2.1 Hz, 0.5 H), 5.86 (dq, J=5.8, 2.2 Hz, 0.5 H),4.88−4.63 (m, 3 H), 3.55−3.39 (m, 1 H), 3.34−3.28 (m, 1 H), 2.61−1.99(m, 7 H), 1.92−1.69 (m, 4 H), 1.51 (s, 18 H), 1.44 (d, J=6.4 Hz, 1.5 H),1.42 (d, J=6.4 Hz, 1.5 H); ESIMS m/z 492.3 ([M+Na]⁺).

Example 13A

Step 1: Preparation of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-7,8-diisobutoxy-9-methyl-2-oxo-oxonan-3-yl]carbamate(C24)

To a solution of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-9-methyl-7,8-bis(2-methylallyloxy)-2-oxo-oxonan-3-yl]carbamate(333 mg, 0.651 mmol) in EtOAc (6.51 mL) was added Pd/C (10% w/w Pd, 34.6mg, 0.033 mmol). The atmosphere was replaced with 1 atm hydrogen(balloon) and the reaction was stirred overnight at room temperature.The reaction mixture was filtered through Celite® and the pad wasflushed with EtOAc. The filtrate was concentrated to provide the titlecompound (313 mg, 93%) as a white, crystalline solid: IR (thin film)2957, 1742, 1724, 1470, 1366, 1347, 1245, 1104 cm⁻¹; ¹H NMR (400 MHz,CDCl₃) δ 4.80 (dd, J=10.5, 8.0 Hz, 1 H), 4.69−4.54 (m, 1 H), 3.60 (dd,J=8.6, 6.2 Hz, 1 H), 3.40−3.21 (m, 4 H), 3.11 (dd, J=8.7, 6.3 Hz, 1 H),2.42−2.25 (m, 1 H), 2.20−2.05 (m, 1 H), 2.01 (m, 1 H), 1.81 (tt, J=12.7,6.3 Hz, 2 H), 1.73−1.55 (m, 3 H), 1.51 (s, 18 H), 1.42−1.32 (m, 3 H),1.01−0.80 (m, 12 H); ¹³C NMR (101 MHz, CDCl₃) δ 170.91, 152.89, 84.27,83.65, 82.64, 80.41, 75.84, 73.15, 57.46, 30.53, 29.07, 28.89, 28.20,27.98, 19.58, 19.54, 19.39, 19.18, 18.12.

Example 13A

Step 2: Preparation of[(3S,7S,8S,9S)-7,8-diisobutoxy-9-methyl-2-oxo-oxonan-3-yl]ammoniumchloride (F6)

Prepared according to the methods described in Example 12A.

Example 13B

Step 1: Preparation of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-8-hydroxy-7-isobutoxy-9-methyl-2-oxo-oxonan-3-yl]carbamate(C25)

To a solution of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-8-hydroxy-9-methyl-7-(2-methylallyloxy)-2-oxo-oxonan-3-yl]carbamate(1.00 g, 2.19 mmol) in EtOAc (4 mL) in a vial was added Pd/C (5% w/w Pd,0.233 g). The vial was evacuated and backfilled with hydrogen (1 atm),then stirred vigorously at room temperature. After stirring overnight,the reaction mixture was filtered through a pad of Celite° andconcentrated to yield a white solid (1.06 g, 95%): IR (thin film) 3448,3224, 2960, 2934, 2877, 1752, 1742, 1723, 1139, 1119 cm⁻¹; ¹H NMR (400MHz, CDCl₃) δ 4.85 (dd, J=9.4, 7.4 Hz, 1 H), 4.73 (dq, J=9.5, 6.3 Hz, 1H), 3.51 (ddd, J=9.5, 7.6, 1.8 Hz, 1 H), 3.35 (dd, J=8.9, 6.7 Hz, 1 H),3.11 (dd, J=8.8, 6.3 Hz, 2 H), 2.93 (d, J=1.8 Hz, 1 H), 2.30 (dtd,J=14.0, 9.8, 1.9 Hz, 1 H), 2.13−2.00 (m, 1 H), 1.95−1.74 (m, 3 H),1.68−1.61 (m, 1 H), 1.61−1.58 (m, 1 H), 1.51 (s, 18 H), 1.42 (d, J=6.3Hz, 3 H), 0.91 (dd, J=6.7, 1.2 Hz, 6 H); ¹³C NMR (101 MHz, CDCl₃) δ170.77, 152.92, 82.71, 82.40, 76.26, 75.85, 73.63, 57.69, 31.43, 31.22,28.69, 27.99, 20.52, 19.41, 19.36, 18.19; HRMS-ESI (m/z) [M+Na]⁺ calcdfor C₂₃H₄₁NNaO₈, 482.2724; found, 482.2718.

The following compounds were prepared and isolated using the methodologydescribed in Example 13B, Step 1:

tert-ButylN-tert-butoxycarbonyl-N-[(3S,7S,8R,9S)-7-hydroxy-8-isobutoxy-9-methyl-2-oxo-oxonan-3-yl]carbamate(C26)

Isolated as a colorless oil (600 mg, 100%): ¹H NMR (400 MHz, CDCl₃)δ4.81 (dd, J=10.5, 6.9 Hz, 1 H), 4.77−4.66 (m, 1 H), 3.60−3.50 (m, 1 H),3.47 (dd, J=8.6, 6.3 Hz, 1 H), 3.40 (dd, J=8.6, 6.7 Hz, 1 H), 3.12 (dd,J=9.5, 7.7 Hz, 1 H), 2.63−2.56 (m, 1 H), 2.36 (ddt, J=13.7, 11.1, 4.9Hz, 1 H), 2.12−1.98 (m, 1 H), 1.95−1.75 (m, 4 H), 1.53−1.50 (m, 1 H),1.51 (s, 18 H), 1.41 (d, J=6.3 Hz, 3 H), 0.93 (dd, J=6.7, 3.3 Hz, 6 H);¹³C NMR (101 MHz, CDCl₃) δ 170.72, 152.82, 85.27, 82.67, 80.81, 72.95,72.82, 57.87, 35.34, 30.89, 29.03, 27.95, 20.13, 19.33, 19.23, 18.26.

Example 13B

Step 2: Preparation of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-7-isobutoxy-8-(4-methoxyphenoxy)-9-methyl-2-oxo-oxonan-3-yl]carbamate(C27)

A vial was charged with tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-8-hydroxy-7-isobutoxy-9-methyl-2-oxo-oxonan-3-yl]carbamate(50 mg, 0.11 mmol), tris(p-methoxyphenyl)bismuth diacetate (106 mg,0.163 mmol), toluene (544 μl) and diacetoxycopper (2.0 mg, 11 μmol).N-cyclohexyl-N-methylcyclohexanamine (46.2 μl, 0.218 mmol) was added andthe reaction was heated to 50° C. and stirred overnight. Theheterogeneous mixture was filtered through a plug of Celite®, thefiltrate concentrated, and the residue purified by automated flashchromatography (0→50% EtOAc/hexanes) to afford a colorless semi-solid(43 mg, 69%): ¹H NMR (400 MHz, CDCl₃) δ 7.01 (d, J=9.1 Hz, 2 H), 6.79(d, J=9.1 Hz, 2 H), 4.96−4.72 (m, 2 H), 4.23 (dd, J=9.6, 7.3 Hz, 1 H),3.76 (s, 3 H), 3.51 (ddd, J=7.1, 5.1, 1.8 Hz, 1 H), 3.24 (dd, J=8.8, 6.7Hz, 1 H), 3.08 (dd, J=8.8, 6.2 Hz, 1 H), 2.44−2.33 (m, 1 H), 2.18 (dddd,J=15.5, 10.0, 8.1, 5.1 Hz, 1 H), 2.05 (dddd, J=13.6, 8.2, 6.3, 1.7 Hz, 1H), 1.83−1.64 (m, 3 H), 1.52 (s, 18 H), 1.34 (d, J=6.3 Hz, 3H), 1.03(ddt, J=15.8, 7.6, 1.9 Hz, 1H), 0.79 (dd, J=18.5, 6.7 Hz, 3H); ¹³C NMR(101 MHz, CDCl₃) δ 170.85, 154.09, 154.02, 152.86, 117.55, 114.37,83.88, 83.14, 82.73, 76.36, 72.80, 57.40, 55.68, 30.57, 28.73, 28.38,27.98, 19.43, 19.29, 19.21, 18.28; IR (thin film) 2977, 1744, 1704,1506, 1140 cm⁻¹; HRMS-ESI (m/z) [M+Na]⁺ calcd for C₃₀H₄₇NNaO₉, 588.3143;found, 588.3146.

Example 13B

Step 3: Preparation of[(3S,7S,8S,9S)-7-isobutoxy-8-(4-methoxyphenoxy)-9-methyl-2-oxo-oxonan-3-yl]ammoniumchloride (F7)

Prepared according to the methods described in Example 12A.

Example 13C

Step 1: Preparation of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-9-methyl-8-(2-methylallyloxy)-2-oxo-7-phenoxy-oxonan-3-yl]carbamate (An alternate method to prepare C16)

A solution of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8R,9S)-7-hydroxy-9-methyl-8-(2-methylallyloxy)-2-oxo-oxonan-3-yl]carbamate(56.0 mg, 0.122 mmol), triphenylbismuth diacetate (137 mg, 0.245 mmol)and diacetoxycopper (4.4 mg, 0.024 mmol) in toluene (1224 μl) wasstirred at 40° C. overnight. The reaction mixture was filtered thruCelite®, the pad washed with toluene (2×10 mL), and the filtrateconcentrated to yield a light blue foam. Purification by columnchromatography (SiO₂; 0→20% EtOAc/hexanes) afforded the title compound(45 mg, 69%) as a white solid: See Compound 16 (Example 12B, Step 1) foranalytical data.

Example 13C

Step 2: Preparation of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-8-isobutoxy-9-methyl-2-oxo-7-phenoxy-oxonan-3-yl]carbamate(An alternate method to prepare C18)

Prepared according to the procedure described for example 12B step 2 andisolated as a clear oil (430 mg; 100%): ¹H NMR (400 MHz, CDCl₃) δ7.32−7.22 (m, 2 H), 6.99−6.86 (m, 3 H), 4.86 (dd, J=10.2, 8.2 Hz, 1 H),4.75 (dq, J=9.7, 6.3 Hz, 1 H), 4.43−4.26 (m, 1 H), 3.66−3.50 (m, 2 H),3.36 (dd, J=8.7, 6.7 Hz, 1 H), 2.44−2.24 (m, 1 H), 2.24−2.08 (m, 1 H),2.04−1.91 (m, 1 H), 1.89−1.56 (m, 3 H), 1.53−1.46 (m, 18 H), 1.44 (d,J=6.3 Hz, 3 H), 1.06 (dd, J=16.0, 7.9 Hz, 1 H), 0.82 (d, J=6.7 Hz, 3 H),0.78 (d, J=6.7 Hz, 3 H); ¹³C NMR (101 MHz, CDCl₃) δ 170.78, 157.65,152.86, 129.44, 121.06, 116.54, 83.33, 83.06, 82.71, 80.56, 72.93,57.27, 30.46, 28.97, 28.85, 27.97, 19.39, 19.28, 19.17, 18.15; HRMS-ESI(m/z) [M+Na]⁺ calcd for C₂₉H₄₅NNaO₈, 558.3037; found, 558.2994.

Example 13C

Step 3: Preparation of[(3S,7S,8S,9S)-8-isobutoxy-9-methyl-2-oxo-7-phenoxy-oxonan-3-yl]ammoniumchloride (An alternative route to prepare F4)

Prepared according to the methods described in Example 12B, Step 3.

Example 13D

Step 1: Preparation of[(2S,3S,4S,8S)-8-[bis(tert-butoxycarbonyl)amino]-3-isobutoxy-2-methyl-9-oxo-oxonan-4-yl]cyclopentanecarboxylate (C28)

To a 10 mL screw-cap vial were added tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8R,9S)-7-hydroxy-8-isobutoxy-9-methyl-2-oxo-oxonan-3-yl]carbamate(200 mg, 0.44 mmol), pyridine (105 μl, 1.31 mmol) and CH₂Cl₂ (2176 μl ),followed by cyclopentanecarbonyl chloride (79 μl, 0.65 mmol). The vialwas sealed under N₂ and the reaction was magnetically stirred overnight.The crude mixture was purified by column chromatography (SiO₂, 1→25%acetone/hexanes) to yield the title compound (203 mg, 84%): ¹H NMR (400MHz, CDCl₃) δ 4.92 (ddd, J=7.4, 5.3, 1.9 Hz, 1 H), 4.85 (dd, J=10.3, 8.0Hz, 1 H), 4.72 (dq, J=9.7, 6.3 Hz, 1 H), 3.45 (dd, J=9.6, 7.6 Hz, 1 H),3.39−3.28 (m, 2 H), 2.72 (p, J=7.9 Hz, 1 H), 2.40−2.26 (m, 1 H),2.17−1.95 (m, 2 H), 1.92−1.69 (m, 8 H), 1.58 (ddd, J=10.7, 5.5, 3.0 Hz,3 H), 1.51 (s, 18 H), 1.41 (d, J=6.3 Hz, 3 H), 1.12−1.00 (m, 1 H), 0.86(t, J=7.0 Hz, 6 H); ¹³C NMR (101 MHz, CDCl₃) δ 175.65, 170.57, 152.78,82.78, 82.17, 80.05, 77.85, 72.95, 57.22, 44.14, 30.53, 30.22, 29.75,29.58, 28.99, 27.97, 25.79, 19.36, 19.28, 18.04; ESIMS m/z 578.4[(M+Na)⁺].

The following compounds were prepared and isolated using the methodologydescribed in Example 13D, Step 1:

[(2S,3S,4S,8S)-8-[bis(tert-butoxycarbonyl)amino]-4-isobutoxy-2-methyl-9-oxo-oxonan-3-yl]cyclopentanecarboxylate (C29)

Isolated as a white solid (98%): mp 101−106° C.; ¹H NMR (400 MHz, CDCl₃)δ 5.12 (dd, J=9.7, 7.8 Hz, 1 H), 4.88−4.73 (m, 2 H), 3.36 (ddd, J=7.5,5.2, 2.0 Hz, 1 H), 3.26 (dd, J =8.7, 6.3 Hz, 1 H), 2.97 (dd, J=8.7, 6.6Hz, 1 H), 2.72 (p, J=7.9 Hz, 1 H), 2.36 (tdd, J=12.5, 10.3, 1.9 Hz, 1H), 2.22−1.98 (m, 2 H), 1.95−1.55 (m, 10 H), 1.51 (s, 18 H), 1.26 (d,J=6.4 Hz, 3 H), 1.02 (ddt, J=15.7, 7.3, 2.0 Hz, 1 H), 0.84 (d, J=6.7 Hz,6 H); ¹³C NMR (101 MHz, CDCl₃) δ 175.60, 170.93, 152.83, 82.71, 81.23,76.10, 75.21, 71.65, 57.37, 43.98, 30.58, 30.13, 29.74, 28.69, 28.36,27.97, 25.81, 25.70, 19.38, 19.34, 18.96, 17.38; ESIMS m/z 578.5([M+Na]⁺).

Example 13D

Step 2: Preparation of[(3S,7S,8S,9S)-7-(cyclopentanecarbonyloxy)-8-isobutoxy-9-methyl-2-oxo-oxonan-3-yl]ammoniumchloride (F8)

Prepared according to the methods described in Example 12A.

The following compounds were prepared and isolated using the methodologydescribed in Example 13D, Step 2:

[(3S,7S,8S,9S)-8-(cyclopentanecarbonyloxy)-7-isobutoxy-9-methyl-2-oxo-oxonan-3-yl]ammoniumchloride (F9)

Example 13E

Step 1: Preparation of (2S,3S,4S,8S)-8-((bistert-butoxycarbonyl)amino)-2-methyl-4-((2-methylallyl)oxy)-9-oxooxonan-3-ylcyclopropanecarboxylate (C30)

To a solution tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-8-hydroxy-9-methyl-7-(2-methylallyloxy)-2-oxo-oxonan-3-yl]carbamate(500 mg, 1.09 mmol) in CH₂C1₂ (2.2 mL) was added pyridine (0.265 mL,3.28 mmol) and cyclopropanecarbonyl chloride (0.149 mL, 1.64 mmol). Theresulting solution was stirred at room temperature for 16 h, thenpurified by automated silica gel column chromatography (0→100%EtOAc/hexanes) to provide a light yellow solid (599 mg, 99%): IR (thinfilm) 2979, 2938, 1737, 1703, 1355, 1159 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ5.14 (dd, J=9.7, 7.8 Hz, 1 H), 4.95−4.66 (m, 4 H), 3.94 (d, J=12.3 Hz, 1H), 3.76 (d, J=12.2 Hz, 1 H), 3.46 (ddd, J=7.6, 5.3, 1.9 Hz, 1 H), 2.37(q, J=11.9, 11.3 Hz, 1 H), 2.21−2.00 (m, 2H), 1.87−1.74 (m, 1 H) 1.71(s, 3H), 1.51 (s, 18 H), 1.28 (d, J=6.3 Hz, 3H), 1.17 (dt, J=6.9, 4.2Hz, 1 H), 1.11−0.97 (m, 4 H), 0.87 (dq, J=6.4, 3.7 Hz, 2 H); ¹³C NMR(101 MHz, CDCl₃) δ 173.98, 170.89, 152.84, 142.11, 112.39, 82.73, 80.01,75.46, 73.07, 71.66, 57.36, 30.57, 28.55, 27.97, 19.41, 19.03, 17.36,12.89, 10.18, 8.49, 8.43.

Example 13E,

Step 2: Preparation of (2S,3S,4S,8S)-8-((bistert-butoxycarbonyl)amino)-4-isobutoxy-2-methyl-9-oxooxonan-3-ylcyclopropanecarboxylate (C31):

Prepared according to the methodology described in Example 13B, Step 1to give the title compound (424 mg, 89%) as a white solid: IR (thinfilm) 2978, 1739, 1706, 1162 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 5.11 (dd,J=9.7, 7.8 Hz, 1 H), 4.88−4.70 (m, 2 H), 3.36 (ddd, J=7.6, 5.2, 2.0 Hz,1 H), 3.30 (dd, J=8.8, 6.1 Hz, 1 H), 2.98 (dd, J=8.8, 6.8 Hz, 1 H), 2.36(dddd, J=13.9, 12.1, 10.1, 1.8 Hz, 1 H), 2.22−1.97 (m, 2 H), 1.85−1.69(m, 2 H), 1.70−1.55 (m, 2 H), 1.51 (s, 18 H), 1.27 (d, J=6.4 Hz, 3 H),1.12−0.96 (m, 3 H), 0.91−0.82 (m, 8 H); ¹³C NMR (101 MHz, CDCl₃) δ173.94, 170.92, 152.84, 82.72, 81.25, 76.30, 75.50, 71.65, 57.37, 30.61,28.63, 27.97, 19.32, 19.27, 19.00, 17.35, 12.89, 8.43, 8.36; HRMS-ESI(m/z) [M+H]⁺ calcd for C₂₇H₄₆NO₉, 528.3167; found, 528.3167.

Example 13E

Step 3: Preparation of[(3S,7S,8S,9S)-8-(cyclopropanecarbonyloxy)-7-isobutoxy-9-methyl-2-oxo-oxonan-3-yl]ammoniumchloride (F10)

Prepared according to the methods described in Example 12A.

Example 13F, Step 1: Preparation of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-9-methyl-7-(2-methylallyloxy)-2-oxo-8-[(E)-4,4,4-trifluorobut-2-enoxy]oxonan-3-yl]carbamate(C32)

A solution of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-8-hydroxy-9-methyl-7-(2-methylallyloxy)-2-oxo-oxonan-3-yl]carbamate(499 mg, 1.09 mmol), (E)-bis tert-butyl (4,4,4-trifluorobut-2-en-1-yl)carbonate (493 mg, 2.18 mmol), dppf (60.5 mg, 0.109 mmol) and Pd₂(dba)₃(49.9 mg, 0.055 mmol) in degassed THF (5453 μl) was heated to 60° C. for1.5 h. The solution was cooled to room temperature and purified byautomated flash chromatography (SiO2; 0→10% EtOAc/hexanes) to yield thetitle compound as a yellow semi-solid (292 mg, 73%): ¹H NMR (400 MHz,CDCl₃) δ 6.44−6.36 (m, 1 H), 5.96−5.78 (m, 1 H), 4.96−4.92 (m, 1 H),4.88−4.85 (m, 1 H), 4.82 (dd, J=10.3, 8.0 Hz, 1 H), 4.73−4.64 (m, 1 H),4.46 (m, 1 H), 4.30−4.21 (m, 1 H), 3.96 (d, J=12.1 Hz, 1 H), 3.79 (d, J=12.1 Hz, 1 H), 3.50−3.39 (m, 2 H), 2.36 (dd, J =12.0, 2.6 Hz, 1 H),2.19−1.98 (m, 2 H), 1.72 (s, 3 H), 1.70−1.59 (m, 2 H), 1.51 (s, 18 H),1.38 (d, J=6.3 Hz, 3 H), 0.97 (dd, J=16.3, 7.7 Hz, 1 H); ¹³C NMR (101MHz, CDCl₃) δ 170.79, 152.89, 142.25, 136.73, 118.34, 118.01, 112.25,84.21, 83.30, 82.74, 77.21, 72.89, 72.49, 71.03, 57.31, 30.50, 28.23,27.98, 19.59, 19.18, 18.04; ESIMS m/z 588.3 ([M+Na]⁺).

Example 13F

Step 2: Preparation of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-7-isobutoxy-9-methyl-2-oxo-8-(4,4,4-trifluorobutoxy)oxonan-3-yl]carbamate(C33)

The tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-9-methyl-7-(2-methylallyloxy)-2-oxo-8-[(E)-4,4,4-trifluorobut-2-enoxy]oxonan-3-yl]carbamate(451 mg, 0.80 mmol) was dissolved in EtOAc (4 mL) in a vial and Pd/C (5%w/w Pd, 85 mg, 0.040 mmol) was added. The vial was evacuated andbackfilled with hydrogen (1 atm), then stirred vigorously at roomtemperature. After stirring for 16 h, the reaction mixture was filteredthrough a pad of Celite® and concentrated to provide a white solid (454mg, 100%): ¹H NMR (400 MHz, CDCl₃) δ 4.80 (dd, J=10.4, 8.0 Hz, 1 H),4.62 (pd, J=6.2, 2.0 Hz, 1 H), 3.83 (dt, J=9.3, 6.0 Hz, 1 H), 3.64 (dt,J =9.3, 6.1 Hz, 1 H), 3.40−3.20 (m, 3 H), 3.08 (dd, J=8.7, 6.2 Hz, 1 H),2.45−2.28 (m, 1 H), 2.25−2.04 (m, 2 H), 2.07−1.95 (m, 1 H), 1.88−1.73(m, 3 H), 1.73−1.57 (m, 3 H), 1.51 (s, 18 H), 1.36 (d, J=6.4 Hz, 3 H),0.95−0.83 (m, 7 H); ¹⁹F NMR (376 MHz, CDCl₃) δ −66.43; ¹³C NMR (101 MHz,CDCl₃) δ 170.88, 152.89, 84.07, 83.91, 82.70, 75.65, 72.75, 71.58,57.39, 31.05, 30.76, 30.50, 28.88, 27.97, 23.07, 23.05, 19.55, 19.47,19.11, 18.09; ESIMS m/z 592.3 ([M+Na]⁺).

Example 13F

Step 3: Preparation of[(3S,7S,8S,9S)-7-isobutoxy-9-methyl-2-oxo-8-(4,4,4-trifluorobutoxy)oxonan-3-yl]ammoniumchloride (F11)

Prepared according to the methods described in Example 12A.

Example 13G, Step 1: Preparation of tert-butylN-[(3S,7S,8S,9S)-7-allyloxy-8-cyclopent-2-en-l-yloxy-9-methyl-2-oxo-oxonan-3-yl]-N-tert-butoxycarbonyl-carbamate(C34)

To a solution of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8R,9S)-8-cyclopent-2-en-1-yloxy-7-hydroxy-9-methyl-2-oxo-oxonan-3-yl]carbamate(200 mg, 0.43 mmol), Pd₂(dba)₃ (39.0 mg, 0.043 mmol) and dppf (47.2 mg,0.085 mmol) in THF (2.1 mL) at room temperature was added allyltert-butyl carbonate (202 mg, 1.28 mmol). The reaction was stirred at60° C. overnight. The reaction mixture was concentrated and purified bycolumn chromatography on SiO₂ (5→25% EtOAc/hexanes) to yield the titlecompound as a yellow oil (160 mg, 74%): IR (thin film) 2978, 2933, 1742,1703; ¹H NMR (400 MHz, CDCl₃) δ 6.05−5.84 (m, 3 H), 5.30−5.24 (m, 1 H),5.17−5.13 (m, 1 H), 4.93−4.76 (m, 2 H), 4.68−4.53 (m, 1 H), 4.13−4.05(m, 1 H), 3.98−3.92 (m, 1 H), 3.54−3.50 (m, 1 H), 3.45−3.38 (m, 1 H),2.52−2.29 (m, 2 H), 2.28−1.89 (m, 4 H), 1.81−1.57 (m, 3 H), 1.51 (s, 18H), 1.39 (d, J=6.4 Hz, 3 H), 1.00−0.88 (m, 1 H); ESIMS m/z 532.4([M+Na]⁺).

Example 13G

Step 2: Preparation of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-8-(cyclopentoxy)-9-methyl-2-oxo-7-propoxy-oxonan-3-yl]carbamate(C35)

Prepared according to the methodology described in Example 13F, Step 2to give the title compound (286 mg, 95%) as a colorless oil): ¹H NMR(400 MHz, CDCl₃) δ 4.79 (dd, J=10.6, 7.9 Hz, 1H), 4.57 (dq, J=9.5, 6.4Hz, 1 H), 4.32−4.25 (m, 1 H), 3.53−3.37 (m, 2 H), 3.35−3.27 (m, 2 H),2.42−2.28 (m, 1 H), 2.19−1.95 (m, 2 H), 1.83−1.53 (m, 12 H), 1.51 (s, 18H), 1.37 (d, J=6.4 Hz, 3 H), 0.92 (t, J=7.4 Hz, 3 H), 0.90−0.87 (m, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 170.93, 152.86, 84.28, 83.25, 82.60,81.26, 73.34, 70.89, 57.47, 32.91, 32.35, 30.50, 28.36, 27.94, 23.33,23.23, 23.19, 19.20, 18.20, 10.76; ESIMS m/z 536.5 ([M+Na]⁺).

Example 13G

Step 3: Preparation of[(3S,7S,8S,9S)-8-(cyclopentoxy)-9-methyl-2-oxo-7-propoxy-oxonan-3-yl]ammoniumchloride (F11)

Prepared according to the methods described in Example 12A.

Example 14

Preparation of (2S,3S,4S,8S)-8-((bistert-butoxycarbonyl)amino)-2-methyl-9-oxooxonane-3,4-diyldicyclopentanecarboxylate (C36)

A 20 mL vial was charged with tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8R,9S)-7,8-dihydroxy-9-methyl-2-oxo-oxonan-3-yl]carbamate(300 mg, 0.74 mmol), CH₂Cl₂ (3.7 mL), and DMAP (182 mg, 1.49 mmol).Cyclopentanecarbonyl chloride (181 μL, 1.49 mmol) was added dropwise tothe colorless solution, which then became dark brown. The reaction flaskwas placed in a room temperature water bath. The reaction mixture wasstirred overnight, concentrated, and partially purified using automatedflash chromatography (SiO₂; 0→100% EtOAc/hexanes) to give fractions thatall contained an impurity derived from the cyclopentanecarbonylchloride. The impure fractions were combined, washed with 1 N HCl, thensaturated NaHCO₃ and brine, and then concentrated to give a colorlessoil (80.2 mg, 18%): IR (thin film) 2954, 1741, 1706, 1140 cm⁻¹; ¹H NMR(400 MHz, CDCl₃) δ 5.24 (dd, J=9.9, 8.1 Hz, 1 H), 5.00 (ddd, J=7.8, 5.2,2.2 Hz, 1 H), 4.92−4.81 (m, 2 H), 2.83−2.72 (m, 2 H), 2.36 (dddd,J=13.8, 12.1, 10.1, 1.8 Hz, 1 H), 2.19−2.00 (m, 2 H), 1.98−1.78 (m, 5H), 1.78−1.54 (m, 13 H), 1.51 (s, 18 H), 1.28 (d, J=6.3 Hz, 3 H), 1.19(ddt, J=16.2, 7.8, 2.2 Hz, 1 H); ¹³C NMR (101 MHz, CDCl₃) δ 175.75,175.55, 170.61, 152.75, 99.98, 82.86, 74.97, 73.67, 71.33, 57.12, 43.91,43.80, 30.46, 30.07, 29.98, 29.93, 29.79, 29.62, 27.96, 25.76, 25.69,19.08, 17.35; HRMS-ESI (m/z) [M+Na]⁺ calcd for C₃,H₄₉NNaO₁₀, 618.3249;found, 618.3250.

Example 14A

Preparation of[(3S,7S,8S,9S)-7,8-bis(cyclopentanecarbonyloxy)-9-methyl-2-oxo-oxonan-3-yl]ammoniumchloride (F12)

Prepared according to the methods described in Example 12A.

Example 15, Step 1: Preparation of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-9-methyl-7-(2-methylallyloxy)-2-oxo-8-[3-oxobut-1-enoxy]oxonan-3-yl]carbamate(C37)

To a 100 mL round bottomed flask were charged tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-8-hydroxy-9-methyl-7-(2-methylallyloxy)-2-oxo-oxonan-3-yl]carbamate(800 mg, 1.75 mmol), DABCO (9.8 mg, 0.087 mmol) and CH₂Cl₂ (8742 μl ).The colorless solution was cooled to 0° C., then but-3-yn-2-one (163 μl,2.10 mmol) was added dropwise over 10 min. The solution became darkbrown. After stirring for 2 h, the reaction mixture was concentrated andpurified by automated flash chromatography (SiO₂; 04100% EtOAc/hexanes)to afford a white solid as an approximate 4:1 mixture of E/Z isomers(0.953 g, 100%): IR (thin film) 2976, 2937, 1742, 1727, 1632, 1139, 1119cm⁻¹; ¹H NMR (Major isomer; 400 MHz, CDCl₃) δ 7.50 (d, J=12.3 Hz, 1 H),5.67 (d, J=12.4 Hz, 1 H), 4.95−4.76 (m, 4 H), 3.94−3.86 (m, 2 H), 3.76(d, J =11.9 Hz, 1 H), 3.46 (ddd, J=7.3, 4.9, 1.9 Hz, 1 H), 2.49−2.32 (m,1 H), 2.21−2.11 (m, 1 H), 2.16 (s, 3H), 2.10−2.01 (m, 1 H), 1.75−1.64(m, 5 H), 1.52 (s, 18 H), 1.35 (d, J=6.4 Hz, 3 H), 1.07−0.96 (m, 1 H);¹³C NMR (101 MHz, CDCl₃) δ 197.43, 170.60, 164.05, 152.85, 141.82,112.84, 108.78, 87.97, 82.88, 81.36, 73.01, 71.03, 57.12, 30.41, 27.97,27.80, 27.50, 19.59, 19.07, 17.96; HRMS-ESI (m/z) [M+Na]⁺ calcd forC₂₇H₄₃NNaO₉, 548.2830; found, 548.2826.

Example 15

Step 2: Preparation of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-7-isobutoxy-9-methyl-2-oxo-8-(3-oxobutoxy)oxonan-3-yl]carbamate(C38)

A round bottomed flask was charged with tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-9-methyl-7-(2-methylallyloxy)-2-oxo-8-[3-oxobut-1-enoxy]oxonan-3-yl]carbamate(954 mg, 1.82 mmol), Pd/C (5% w/w Pd, 193 mg, 0.091 mmol), and EtOAc (9mL). The flask was evacuated and backfilled with N₂, then evacuated andbackfilled with H₂. The reaction mixture was stirred vigorously at roomtemperature overnight. The crude reaction mixture was filtered through aplug of Celite® and the filtrate concentrated to give a crude solid. Thesolid was purified by automated flash chromatography (SiO₂; 0→100%EtOAc/hexanes) to give a white solid (785 mg, 82%): IR (thin film) 2977,2937, 1743, 1704, 1356, 1141 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 4.80 (dd,J=10.5, 8.0 Hz, 1 H), 4.65−4.53 (m, 1 H), 4.02 (dt, J=9.5, 6.0 Hz, 1 H),3.89 (ddd, J=9.5, 7.1, 5.7 Hz, 1 H), 3.36−3.23 (m, 3 H), 3.11 (dd, J=8.8, 6.2 Hz, 1 H), 2.74−2.56 (m, 2 H), 2.41−2.26 (m, 1 H), 2.17 (s, 3H), 2.15−2.06 (m, 1 H), 2.03−1.96 (m, 1 H), 1.87−1.76 (m, 1 H),1.73−1.60 (m, 2 H), 1.51 (d, J=2.4 Hz, 18 H), 1.35 (d, J=6.3 Hz, 3 H),0.91 (dd, J=6.7, 1.4 Hz, 6 H), 0.87 (dd, J=7.1, 1.9 Hz, 1 H); ¹³C NMR(101 MHz, CDCl₃) δ 207.19, 170.86, 152.87, 84.02, 83.99, 82.67, 75.65,72.76, 68.23, 57.39, 44.20, 30.49, 28.89, 28.06, 27.97, 19.56, 19.49,19.13, 18.02; HRMS-ESI (m/z) [M+Na]⁺ calcd for C₂₇H₄₇NNaO₉, 552.3143;found, 552.3158.

Example 15

Step 3: Preparation of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-7-isobutoxy-8-(3-methoxybutoxy)-9-methyl-2-oxo-oxonan-3-yl]carbamate(C39)

The tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-7-isobutoxy-9-methyl-2-oxo-8-(3-oxobutoxy)oxonan-3-yl]carbamate(400 mg, 0.76 mmol) was dissolved in MeOH (3.8 mL) and cooled to 0° C.under N₂, and NaBH₄ (5 mg, 1.72 mmol) was added in one portion. Thereaction was stirred for 2.5 h and then quenched by the addition ofsaturated aqueous NH₄Cl solution. The mixture was extracted with EtOAc,and the extracts were washed with brine, dried over Na₂SO₄, filtered,and concentrated to afford tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-8-(3-hydroxybutoxy)-7-isobutoxy-9-methyl-2-oxo-oxonan-3-yl]carbamate(382 mg, 95%) as a colorless oil, which was used without furtherpurification. An oven-dried round bottom flask was charged with thediastereomeric mixture of the alcohol (405 mg, 0.762 mmol), ProtonSponge® (653 mg, 3.05 mmol), and CH₂Cl₂ (5 mL). Trimethyloxoniumtetrafluoroborate (225 mg, 1.52 mmol) was added in one portion to thecolorless solution. A white suspension formed, and the mixture wasstirred at room temperature. After stirring for 6 h, the reaction wasquenched by the addition of saturated aqueous NaHCO₃ (3 mL) and thephases were separated. The aqueous layer was extracted with CH₂Cl₂ andthe combined organic layers were washed with brine, passed through aphase separator cartridge, concentrated, and purified by automated flashchromatography (SiO₂; 0→100% EtOAc/hexanes) to afford a light pink oilas a mixture of diastereomers (328 mg, 79%): IR (thin film) 2935, 1745,1706, 1142 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 4.91−4.75 (m, 1 H), 4.71−4.51(m, 1 H), 4.02−3.93 (m, 1 H), 3.91−3.78 (m, 1 H), 3.74−3.59 (m, 1 H),3.50−3.36 (m, 1 H), 3.36−3.31 (m, 2 H), 3.30 (s, 2 H), 3.29−3.22 (m, 1H), 3.13 (tt, J =8.7, 6.1 Hz, 1 H), 2.43−2.27 (m, 1 H), 2.18−1.92 (m, 2H), 1.90−1.75 (m, 1 H), 1.75−1.59 (m, 4 H), 1.51 (s, 18 H), 1.43−1.33(m, 3 H), 1.18 (dd, J =6.2, 2.9 Hz, 1H), 1.14−1.12 (m, 2H), 0.96−0.85(m, 7H); ¹³C NMR (101 MHz, CDCl₃) δ 170.92, 170.90, 152.89, 85.49,84.82, 84.27, 84.14, 83.71, 82.68, 82.66, 82.61, 76.35, 75.95, 75.91,75.53, 73.48, 73.11, 72.87, 61.27, 58.72, 57.44, 57.40, 56.51, 36.20,32.47, 30.57, 30.54, 29.01, 28.87, 28.84, 28.29, 28.24, 19.63, 19.54,19.49, 19.37, 19.15, 18.02, 17.92, 17.72, 15.73, 13.96; HRMS-ESI (m/z)[M+Na]⁺ calcd for C₂₈H₅₁,NNaO₉, 568.3456; found, 568.3453.

Example 15

Step 4: Preparation of[(3S,7S,8S,9S)-8-(3-methoxybutoxy)-7-isobutoxy-9-methyl-2-oxo-oxonan-3-yl]ammoniumchloride (F13)

Prepared using the methodology described in Example 12A.

Example 16A

Preparation of3-hydroxy-4-methoxy-N-((3S,7S,8S,9S)-9-methyl-7,8-bis((2-methylallyl)oxy)-2-oxooxonan-3-yl)pyridine-2-carboxamide(F14)

To a suspension of the[(3S,7S,8S,9S)-9-methyl-7,8-bis(2-methylallyloxy)-2-oxo-oxonan-3-yl]ammoniumchloride (256 mg, 0.736 mmol) and 3-hydroxy-4-methoxypicolinic acid (137mg, 0.809 mmol) in CH₂Cl₂ (6.0 ml) was added Hünig's base (0.422 ml,2.42 mmol) followed by PyBOP (421 mg, 0.809 mmol). The reaction wasstirred at room temperature for 90 min. The solvent was then removed andthe resulting crude residue was purified by automated silica gel columnchromatography (1466% acetone/hexanes) to afford the title compound (246mg, 72%) as a white foam.

Example 16B

Preparation ofN-[(3S,7S,8S,9S)-7,8-dibenzyloxy-9-methyl-2-oxo-oxonan-3-yl]-3-hydroxy-4-methoxypyridine-2-carboxamide(F15)

To a suspension of the[(3S,7S,8S,9S)-7,8-dibenzyloxy-9-methyl-2-oxo-oxonan-3-yl]ammoniumchloride (220 mg, 0.52 mmol) and 3-hydroxy-4-methoxypicolinic acid (124mg, 0.733 mmol) in CH₂Cl₂ (5.2 mL) was added N-methylmorpholine (0.346mL, 3.14 mmol) followed by HATU (299 mg, 0.786 mmol). The mixture wasstirred at room temperature for 5 h, then the solvent was removed andthe crude residue was purified by automated silica gel columnchromatography (5420% acetone/hexanes) to afford the title compound (124mg, 44.3%) as a hard white foam.

Example 17A

Preparation of[4-methoxy-2-[[(3S,7S,8S,9S)-9-methyl-7,8-bis(2-methylallyloxy)-2-oxo-oxonan-3-yl]carbamoyl]-3-pyridyl]oxymethylacetate (F16)

To a screw-cap vial were added3-hydroxy-4-methoxy-N-((3S,7S,8S,9S)-9-methyl-7,8-bis((2-methylallyl)oxy)-2-oxooxonan-3-yl)pyridine-2-carboxamide(110 mg, 0.24 mmol) and K₂CO₃ (65.7 mg, 0.476 mmol), followed by acetone(2.38 ml). Then, bromomethyl acetate (33 μl, 0.34 mmol) was addeddropwise and the reaction was heated to 50° C. for 1 h. The reactionmixture was cooled to room temperature, filtered through a plug of glasswool, and then the solvent was removed. The crude residue was purifiedby automated silica gel column chromatography (1→50% acetone/hexanes) toafford the title compound (98.9 mg, 78%) as a colorless oil.

Example 17B

Preparation of[4-methoxy-2-[[(3S,7S,8S,9S)-9-methyl-7,8-bis(2-methylallyloxy)-2-oxo-oxonan-3-yl]carbamoyl]-3-pyridyl]oxymethyl-2-methylpropanoate(F17)

To a screw-cap vial were added3-hydroxy-4-methoxy-N-((3S,7S,8S,9S)-9-methyl-7,8-bis((2-methylallyl)oxy)-2-oxooxonan-3-yl)pyridine-2-carboxamide(110 mg, 0.24 mmol), powdered Na₂CO₃ (50.4 mg, 0.476 mmol), and NaI (5.4mg, 0.036 mmol) followed by acetone (2.38 ml). Then, chloromethylisobutyrate (0.042 ml, 0.33 mmol) was added dropwise and the reactionwas heated to 50° C. for 14 h. The reaction mixture was cooled to roomtemperature, filtered through a plug of glass wool, and then the solventwas evaporated. The crude residue was purified by automated silica gelcolumn chromatography (1→50% acetone/hexanes) to afford the titlecompound (127.9 mg, 96%) as a colorless oil.

Example 17C

Preparation of[2-[[(3S,7S,8S,9S)-8-isobutoxy-9-methyl-7-(2-methylallyloxy)-2-oxo-oxonan-3-yl]carbamoyl]-4-methoxy-3-pyridyl]acetate (F18)

To a screw-cap vial were added3-hydroxy-N-[(3S,7S,8S,9S)-8-isobutoxy-9-methyl-7-(2-methylallyloxy)-2-oxo-oxonan-3-yl]-4-methoxypyridine-2-carboxamide(17.0 mg, 0.037 mmol) and CH₂C1₂ (0.52 mL), followed by DMAP (0.89 mg,0.73 μmol) and TEA (10.2 μl, 0.073 mmol). Then, acetyl chloride (3.9 μ1,0.055 mmol) was added and the reaction was stirred at room temperaturefor 3 h. The mixture was diluted with CH₂Cl₂ and quenched by pouringinto saturated aqueous NH₄Cl. The organic phase was separated and theaqueous phase was extracted with CH₂Cl₂ three times. The combinedorganic phases were passed through a phase separator and the solvent wasthen evaporated. The resulting crude residue was purified by automatedsilica gel column chromatography (1→50% acetone/hexanes) to afford thetitle compound (15.7 mg, 85%) as a colorless oil.

Example 17D

Preparation of[2-[[(3S,7S,8S,9S)-7-(cyclopentoxy)-9-methyl-2-oxo-8-propoxy-oxonan-3-yl]carbamoyl]-4-methoxy-3-pyridyl]3-methoxypropanoate (F19)

To a screw-cap vial were addedN-[(3S,7S,8S,9S)-7-(cyclopentoxy)-9-methyl-2-oxo-8-propoxy-oxonan-3-yl]-3-hydroxy-4-methoxypyridine-2-carboxamide(51.7 mg, 0.111 mmol) and CH₂Cl₂ (1.1 mL), followed by DMAP (6.8 mg,0.056 mmol) and TEA (30.9 μl, 0.223 mmol). Then, 3-methoxypropanoylchloride (24.1 μl, 0.223 mmol) was added dropwise and the reaction wasstirred at room temperature for 3 h. The mixture was diluted with CH₂Cl₂and quenched by pouring into saturated aqueous NH₄Cl. The organic phasewas separated and the aqueous phase was extracted with CH₂Cl₂ threetimes. The combined organic phases were passed through a phase separatorand the solvent was then evaporated. The resulting crude residue waspurified by automated silica gel column chromatography (1→50%acetone/hexanes) to afford the title compound (58.7 mg, 96%) as a whitesolid.

Example 18

Preparation of tert-butyl((3aS,4S,7S,10aS)-4-methyl-6-oxo-2-phenyloctahydro-[1,3]dioxolo[4,5-c]oxonin-7-yl)carbamate.

To a solution of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8R,9S)-7,8-dihydroxy-9-methyl-2-oxo-oxonan-3-yl]carbamate(250 mg, 0.620 mmol) in CH₂Cl₂ (3 mL) were added 4-methylbenzenesulfonicacid (21.34 mg, 0.124 mmol), benzaldehyde (315 μl, 3.10 mmol), and MgSO₄(100 mg), and the reaction was stirred at ambient temperature for 2 h.The reaction mixture was filtered through a plug of Celite®,concentrated and purified via silica gel chromatography (gradient,hexanes/EtOAc) to afford the title compound (240 mg, 99%) as a whitesolid:¹H NMR (400 MHz, CDCl₃) δ 7.47 (tdd, J=5.2, 4.2, 2.8 Hz, 2 H),7.38 (dp, J=5.7, 1.5 Hz, 3 H), 5.79 (s, 1 H), 5.31−5.15 (m, 2 H), 4.17(ddd, J=12.4, 7.9, 5.0 Hz, 1 H), 3.90 (ddd, J=11.4, 6.9, 3.0 Hz, 1 H),3.68 (dd, J=9.7, 6.9 Hz, 1 H), 2.30 (ddd, J=17.7, 10.1, 4.5 Hz, 1 H),2.10−1.89 (m, 2 H), 1.84−1.57 (m, 2 H), 1.49 (d, J=6.3 Hz, 3 H), 1.45(s, 9 H), 1.43−1.31 (m, 1 H); ¹³C NMR (101 MHz, CDCl₃) δ 173.75, 154.81,136.32, 129.69, 128.44, 126.79, 102.84, 83.62, 80.04, 79.70, 71.69,54.23, 34.42, 32.94, 30.94, 28.33, 19.76, 18.33; ESIMS m/z 414 ([M+H]⁺).

Example 19

Preparation of tert-butylN-[(3aS,4S,7S,10aS)-2-ethyl-4-methyl-6-oxo-4,7,8,9,10,10a-hexahydro-3aH-[1,3]dioxolo[4,5-c]oxonin-7-yl]-N-tert-butoxycarbonyl-carbamate.

To a solution of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8R,9S)-7,8-dihydroxy-9-methyl-2-oxo-oxonan-3-yl]carbamate(250 mg, 0.620 mmol) in CH₂Cl₂ (3.1 mL) were added4-methylbenzenesulfonic acid (21.34 mg, 0.124 mmol), propionaldehyde(225 μl, 3.10 mmol), and MgSO₄ (100 mg), and the reaction was stirred atambient temperature for 2 h. The reaction mixture was filtered through aplug of Celite® , concentrated and purified via silica gelchromatography (gradient, hexanes/EtOAc) to afford the title compound(217 mg, 79%) as a sticky, colorless oil: ¹H NMR (400 MHz, CDCl₃)δ 4.93(dq, J=9.6, 6.3 Hz, 1 H), 4.83 (t, J=4.6 Hz, 1 H), 4.67 (dd, J=12.3, 4.8Hz, 1 H), 3.69 (ddd, J=11.3, 6.8, 2.7 Hz, 1 H), 3.47 (dd, J=9.6, 6.9 Hz,1 H), 2.39 (dddd, J =13.9, 12.2, 6.6, 1.6 Hz, 1 H), 2.16−1.91 (m, 3 H),1.80−1.59 (m, 4 H), 1.51 (s, 18 H), 1.43 (d, J=6.2 Hz, 3 H), 0.94 (t,J=7.6 Hz, 3 H); ¹³C NMR (101 MHz, CDCl₃) δ 171.36, 152.87, 104.15,83.14, 82.76, 79.54, 72.13, 59.10, 34.45, 30.54, 27.97, 26.41, 21.04,18.53, 7.93; ESIMS m/z 444 ([M+H]⁺).

Example 20

Preparation of A) tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-7-(3-fluorophenoxy)-8-hydroxy-9-methyl-2-oxo-oxonan-3-yl]carbamateand B) tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8R,9S)-8-(3-fluorophenoxy)-7-hydroxy-9-methyl-2-oxo-oxonan-3-yl]carbamate.

To a solution of tris(3-fluorophenyl)bismuthine (1.056 g, 2.137 mmol) inCH₂Cl₂ (7.12 mL) was added peracetic acid (0.503 mL, 2.421 mmol) at 0°C., and the solution was warmed to room temperature and stirred for 20min. To the resulting solution were added tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8R,9S)-7,8-dihydroxy-9-methyl-2-oxo-oxonan-3-yl]carbamate(575 mg, 1.42 mmol) and diacetoxycopper (52 mg, 0.28 mmol), and theresulting blue-green slurry was stirred at room temperature for 16 h,warmed to 40° C., and stirred at 40° C. for 4 h. The reaction mixturewas filtered through a plug of Celite® and any peroxides in the filtratewere quenched by the addition of saturated aqueous sodium bisulfite(NaHSO₃). The biphasic mixture was passed through a phase separatorcartridge and concentrated. The crude residue was purified by silica gelchromatography (gradient, petroleum ether/MTBE) to afford the titlecompounds A and B.

Compound A (117 mg, 16%) was isolated as a light yellow oil: ¹H NMR (400MHz, CDCl₃) δ 7.22 (td, J=8.2, 6.8 Hz, 1 H), 6.74−6.61 (m, 3 H), 4.95(t, J=8.5 Hz, 1 H), 4.84 (dq, J =9.5, 6.2 Hz, 1 H), 4.17 (ddd, J=7.8,6.0, 1.9 Hz, 1 H), 3.86 (ddd, J=9.6, 7.6, 2.3 Hz, 1 H), 2.64 (d, J=2.7Hz, 1 H), 2.29 (dddd, J=14.0, 11.2, 8.6, 1.7 Hz, 1 H), 2.35−2.24 (m, 1H), 2.13−1.99 (m, 2 H), 1.89 (dddd, J=17.3, 15.9, 8.6, 3.9 Hz, 1 H),1.68−1.55 (m, 1 H), 1.52 (s, 18 H), 1.47 (d, J=6.3 Hz, 3 H); ¹⁹F NMR(376 MHz, CDCl₃) δ −111.22; ESIMS m/z 498 ([M+H]⁺).

Compound B (214 mg, 30%) was isolated as a colorless oil: ¹H NMR (400MHz, CDCl₃) δ 7.23 (td, J=8.3, 6.7 Hz, 1 H), 6.83 (ddd, J=8.4, 2.5, 0.9Hz, 1 H), 6.77 (dt, J=10.8, 2.4 Hz, 1 H), 6.70 (dddd, J=8.3, 7.4, 2.4,1.2 Hz, 1 H), 4.95−4.83 (m, 2 H), 4.27 (dd, J=9.5, 7.8 Hz, 1 H), 3.88(ddt, J=8.1, 5.3, 2.3 Hz, 1 H), 2.45−2.33 (m, 1 H), 2.16−2.13 (m, 1 H),2.13−1.97 (m, 2 H), 1.83 (dtd, J=12.2, 9.4, 8.2, 6.1 Hz, 2 H), 1.52 (s,18 H), 1.49−1.39 (m, 1 H), 1.32 (d, J=6.4 Hz, 3 H); ¹⁹F NMR (376 MHz,CDCl₃) δ −110.94; ESIMS m/z 498 ([M+H]⁺).

Example 21

Preparation of tert-butylN-[(3S,7S,8S,9S)-8-(4-bromophenoxy)-9-methyl-2-oxo-7-propoxy-oxonan-3-yl]-N-tert-butoxycarbonyl-carbamate.

To a solution of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-9-methyl-2-oxo-8-phenoxy-7-propoxy-oxonan-3-yl]carbamate(523 mg, 1.003 mmol) in CH₂Cl₂ (5 mL) was added NBS (357 mg, 2.005mmol). The vial was wrapped in aluminum foil and stirred at roomtemperature for 16 h. An additional portion of NBS (357 mg, 2 mmol) wasadded and the reaction was stirred at room temperature for an additional3 h, concentrated, and the residue purified by silica gel chromatography(gradient, hexanes/EtOAc) to afford the title compound (567 mg, 94%): ¹HNMR (400 MHz, CDCl₃) δ 7.39−7.30 (m, 2 H), 7.00−6.91 (m, 2 H), 4.90−4.78(m, 2 H), 4.28 (dd, J=9.7, 7.3 Hz, 1 H), 3.52 (ddd, J=7.2, 5.2, 1.9 Hz,1 H), 3.44 (dt, J=9.0, 6.6 Hz, 1 H), 3.20 (dt, J=9.0, 6.5 Hz, 1 H),2.48−2.33 (m, 1 H), 2.23−2.11 (m, 1 H), 2.12−2.00 (m, 1 H), 1.82−1.65(m, 2 H), 1.52 (s, 18 H), 1.47−1.36 (m, 2 H), 1.31 (d, J=6.4 Hz, 3 H),1.12−0.99 (m, 1 H), 0.77 (t, J=7.4 Hz, 3 H); ¹³C NMR (101 MHz, CDCl₃) δ170.80, 158.94, 152.87, 132.12, 118.28, 113.38, 83.31, 82.96, 82.76,72.40, 71.28, 57.34, 30.53, 27.98, 23.15, 19.23, 18.17, 10.56; ESIMS m/z622 ([M+H]⁺).

Example 22

Preparation of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-9-methyl-2-oxo-8-(4-phenylphenoxy)-7-propoxy-oxonan-3-yl]carbamate.

A vial was charged with tert-butylN-[(3S,7S,8S,9S)-8-(4-bromophenoxy)-9-methyl-2-oxo-7-propoxy-oxonan-3-yl]-N-tert-butoxycarbonyl-carbamate(34 mg, 0.057 mmol), phenylboronic acid (19 mg, 0.156 mmol), Na₂CO₃(18.0 mg, 0.170 mmol) and Pd(PPh₃)₄ (6.54 mg, 5.66 μmol). The vial wasevacuated and backfilled with N₂ (repeated 3×), dioxane (425 μl) andwater (142 μl) were added, and the vial was fitted with an air condenserand the reaction mixture was heated at 80° C. for 3 h. The cooledreaction mixture was diluted with CH₂Cl₂, passed through a phaseseparator cartridge, concentrated, and the residue purified by silicagel chromatography (gradient, hexanes/EtOAc) to afford the titlecompound (25 mg, 74%) as a white solid: ¹H NMR (400 MHz, CDCl₃) δ7.59−7.53 (m, 2 H), 7.51−7.46 (m, 2 H), 7.47−7.37 (m, 2 H), 7.36−7.26(m, 1 H), 7.18−7.09 (m, 2 H), 4.94−4.79 (m, 2 H), 4.40 (dd, J=9.6, 7.3Hz, 1 H), 3.56 (ddd, J=7.1, 5.1, 1.9 Hz, 1 H), 3.47 (dt, J=9.0, 6.6 Hz,1 H), 3.26 (dt, J=9.1, 6.5 Hz, 1 H), 2.49−2.35 (m, 1 H), 2.25−2.12 (m, 1H), 2.13−2.01 (m, 1 H), 1.86−1.66 (m, 2 H), 1.52 (s, 18 H), 1.48−1.39(m, 2 H), 1.37 (d, J=6.3 Hz, 3H), 1.08 (ddt, J=15.9, 7.5, 1.9 Hz, 1H),0.77 (t, J=7.4 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 170.86, 159.35,152.89, 140.82, 134.28, 128.69, 127.99, 126.74, 126.66, 116.75, 83.07,83.04, 82.75, 72.67, 71.42, 57.42, 30.59, 28.76, 27.99, 23.19, 19.30,18.26, 10.57; ESIMS m/z 620 ([M+Na]⁺).

Example 23

Preparation of tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-8-methoxy-9-methyl-7-(2-methylallyloxy)-2-oxo-oxonan-3-yl]carbamate.

To a solution of a tert-butylN-tert-butoxycarbonyl-N-[(3S,7S,8S,9S)-8-hydroxy-9-methyl-7-(2-methylallyloxy)-2-oxo-oxonan-3-yl]carbamate(1.00 g, 2.19 mmol) in CH₂C1₂ (21.86 ml) at 0° C. was added ProtonSponge® (0.937 g, 4.37 mmol) followed by trimethyloxoniumtetrafluoroborate (0.485 g, 3.28 mmol). The mixture was stirred at 0° C.for 30 min, warmed to ambient temperature, stirred for an additional 30min, and then poured into sat. aqueous NaHCO₃ (50 mL) and extracted withCH₂Cl₂ (3×50 mL). The combined organic extracts were washed with 10%NaHSO₄ (2×50 mL), washed with brine (50 mL), and dried by passingthrough a phase-separation cartridge. The filtrate was concentrated andthe crude foam was purified via flash chromatography (SiO₂, 0→35%EtOAc/hexane) to afford the title product as a clear oil (1.03 g, 100%):¹H NMR (400 MHz, CDCl₃) δ 4.98 (dd, J=2.0, 0.9 Hz, 1 H), 4.91−4.85 (m,1 H), 4.82 (dd, J=10.4, 8.1 Hz, 1 H), 4.62 (dq, J=9.7, 6.3 Hz, 1 H),3.98 (d, J=12.1 Hz, 1 H), 3.86 (d, J=12.1 Hz, 1 H), 3.56 (s, 3 H), 3.40(ddd, J=7.0, 5.1, 1.7 Hz, 1 H), 3.27 (dd, J=9.6, 7.3 Hz, 1 H), 2.43−2.29(m, 1 H), 2.17−1.97 (m, 2 H), 1.77 (s, 3 H), 1.74−1.58 (m, 2 H), 1.51(s, 18 H), 1.39 (d, J=6.3 Hz, 3 H), 1.01−0.88 (m, 1 H); ¹³C NMR (101MHz, CDCl₃) δ 170.84, 152.88, 142.53, 112.15, 85.57, 83.24, 82.65,73.03, 72.89, 61.32, 57.36, 30.55, 28.40, 27.96, 19.57, 19.17, 17.87;HRMS-ESI (m/z) [M+Na]⁺ calcd for C₂₄H₄,NNaO₈, 494.2734; found, 494.2724.

Example A

Evaluation of Fungicidal Activity: Leaf Blotch of Wheat (Mycosphaerellagraminicola; Anamorph: Septoria trilici; Bayer code SEPTTR):

Technical grades of materials were dissolved in acetone, which were thenmixed with nine volumes of water containing 110 ppm Triton X-100. Thefungicide solutions were applied onto wheat seedlings using an automatedbooth sprayer to run-off All sprayed plants were allowed to air dryprior to further handling. All fungicides were evaluated using theaforementioned method for their activity vs. all target diseases. Wheatleaf blotch and brown rust activity were also evaluated using trackspray applications, in which case the fungicides were formulated as ECformulations, containing 0.1% Trycol 5941 in the spray solutions.

Wheat plants (variety Yuma) were grown from seed in a greenhouse in 50%mineral soil/50% soil-less Metro mix until the first leaf was fullyemerged, with 7-10 seedlings per pot. These plants were inoculated withan aqueous spore suspension of Septoria tritici either prior to or afterfungicide treatments. After inoculation the plants were kept in 100%relative humidity (one day in a dark dew chamber followed by two tothree days in a lighted dew chamber at 20° C.) to permit spores togerminate and infect the leaf. The plants were then transferred to agreenhouse set at 20° C. for disease to develop. When disease symptomswere fully expressed on the 1^(st) leaves of untreated plants, infectionlevels were assessed on a scale of 0 to 100 percent disease severity.Percent disease control was calculated using the ratio of diseaseseverity on treated plants relative to untreated plants.

Example B

Evaluation of Fungicidal Activity: Wheat Brown Rust (Puccinia triticina;Synonym: Puccinia recondita f sp. tritici; Bayer code PUCCRT):

Wheat plants (variety Yuma) were grown from seed in a greenhouse in 50%mineral soil/50% soil-less Metro mix until the first leaf was fullyemerged, with 7-10 seedlings per pot. These plants were inoculated withan aqueous spore suspension of Puccinia triticina either prior to orafter fungicide treatments. After inoculation the plants were kept in adark dew room at 22° C. with 100% relative humidity overnight to permitspores to germinate and infect the leaf. The plants were thentransferred to a greenhouse set at 24° C. for disease to develop.Fungicide formulation, application and disease assessment followed theprocedures as described in the Example A.

Example C

Evaluation of Fungicidal Activity: Wheat Glume Blotch (Leptosphaerianodorum; Bayer code LEPTNO):

Wheat plants (variety Yuma) were grown from seed in a greenhouse in 50%mineral soil/50% soil-less Metro mix until the first leaf was fullyemerged, with 7-10 seedlings per pot. These plants were inoculated withan aqueous spore suspension of Leptosphaeria nodorum 24 hr afterfungicide treatments. After inoculation the plants were kept in 100%relative humidity (one day in a dark dew chamber followed by two days ina lighted dew chamber at 20° C.) to permit spores to germinate andinfect the leaf The plants were then transferred to a greenhouse set at20° C. for disease to develop. Fungicide formulation, application anddisease assessment followed the procedures as described in the ExampleA.

Example D

Evaluation of Fungicidal Activity: Apple Scab (Venturia inaequalis;Bayer code VENTIN):

Apple seedlings (variety McIntosh) were grown in soil-less Metro mix,with one plant per pot. Seedlings with two expanding young leaves at thetop (older leaves at bottom of the plants were trimmed) were used in thetest. Plants were inoculated with a spore suspension of Venturiainaequalis 24 hr after fungicide treatment and kept in a 22° C. dewchamber with 100% RH for 48 hr, and then moved to a greenhouse set at20° C. for disease to develop. Fungicide formulation, application anddisease assessment on the sprayed leaves followed the procedures asdescribed in the Example A.

Example E

Evaluation of Fungicidal Activity: Grape Powdery Mildew (Uncinulanecator; Bayer code UNCINE):

Grape seedlings (variety Carignane) were grown in soil-less Metro mix,with one plant per pot, and used in the test when approximately onemonth old. Plants were inoculated 24 hr after fungicide treatment byshaking spores from infected leaves over test plants. Plants weremaintained in a greenhouse set at 20° C. until disease was fullydeveloped. Fungicide formulation, application and disease assessment onthe sprayed leaves followed the procedures as described in the ExampleA.

Example F

Evaluation of Fungicidal Activity: Powdery Mildew of Cucumber (Erysiphecichoracearum; Bayer code ERYSCI):

Cucumber seedlings (variety Bush Pickle) were grown in soil-less Metromix, with one plant per pot, and used in the test when 12 to 14 daysold. Plants were inoculated with a spore suspension 24 hr followingfungicide treatments. After inoculation the plants remained in thegreenhouse set at 20° C. until disease was fully expressed. Fungicideformulation, application and disease assessment on the sprayed leavesfollowed the procedures as described in the Example A.

Example G

Evaluation of Fungicidal Activity: Leaf Spot of Sugar Beets (Cercosporabeticola; Bayer code CERCBE):

Sugar beet plants (variety HH88) were grown in soil-less Metro mix andtrimmed regularly to maintain a uniform plant size prior to test. Plantswere inoculated with a spore suspension 24 hr after fungicidetreatments. Inoculated plants were kept in a dew chamber at 22° C. for48 hr then incubated in a greenhouse set at 24° C. under a clear plastichood with bottom ventilation until disease symptoms were fullyexpressed. Fungicide formulation, application and disease assessment onthe sprayed leaves followed the procedures as described in the ExampleA.

Example H

Evaluation of Fungicidal Activity: Asian Soybean Rust (Phakopsorapachyrhizi; Bayer code PHAKPA):

Technical grades of materials were dissolved in acetone, which were thenmixed with nine volumes of water containing 0.011% Tween 20. Thefungicide solutions were applied onto soybean seedlings using anautomated booth sprayer to run-off. All sprayed plants were allowed toair dry prior to further handling.

Soybean plants (variety Williams 82) were grown in soil-less Metro mix,with one plant per pot. Two weeks old seedlings were used for testing.Plants were inoculated either 3 days prior to or 1 day after fungicidetreatments. Plants were incubated for 24 h in a dark dew room at 22° C.and 100% RH then transferred to a growth room at 23 ° C. for disease todevelop. Disease severity was assessed on the sprayed leaves.

Example I

Evaluation of Fungicidal Activity: Wheat Powdery Mildew (Blumeriagraminis fsp. tritici; Synonym: Erysiphe graminis fsp. tritici; BayerCode ERYSGT):

Wheat plants (variety Yuma) were grown from seed in a greenhouse in 50%mineral soil/50% soil-less Metro mix until the first leaf was fullyemerged, with 7-10 seedlings per pot. These plants were inoculated bydusting with infected stock plants 24 hr after fungicide treatments.After inoculation the plants were kept in a greenhouse set at 20° C. fordisease to develop. Fungicide formulation, application and diseaseassessment on the sprayed leaves followed the procedures as described inthe Example A.

Example J

Evaluation of Fungicidal Activity: Barley Powdery Mildew (Blumeriagraminis fsp. hordei; Synonym: Erysiphe graminis fsp. hordei; Bayer CodeERYSGH):

Barley seedlings (variety Harrington) were propagated in soil-less Metromix, with each pot having 8 to 12 plants, and used in the test whenfirst leaf was fully emerged. Test plants were inoculated by dustingwith infected stock plants 24 hr after fungicide treatments. Afterinoculation the plants were kept in a greenhouse set at 20° C. fordisease to develop. Fungicide formulation, application and diseaseassessment on the sprayed leaves followed the procedures as described inthe Example A.

Example K

Evaluation of Fungicidal Activity: Barley Scald (Rhyncosporium secalis;Bayer Code RHYNSE):

Barley seedlings (variety Harrington) were propagated in soil-less Metromix, with each pot having 8 to 12 plants, and used in the test whenfirst leaf was fully emerged. Test plants were inoculated by an aqueousspore suspension of Rhyncosporium secalis 24 hr after fungicidetreatments. After inoculation the plants were kept in a dew room at 20°C. with 100% relative humidity for 48 hr. The plants were thentransferred to a greenhouse set at 20° C. for disease to develop.Fungicide formulation, application and disease assessment on the sprayedleaves followed the procedures as described in the Example A.

Example L

Evaluation of Fungicidal Activity: Rice Blast (Magnaporthe grisea;Anamorph: Pyricularia oryzae; Bayer Code PYRIOR):

Rice seedlings (variety Japonica) were propagated in soil-less Metromix, with each pot having 8 to 14 plants, and used in the test when 12to 14 days old. Test plants were inoculated with an aqueous sporesuspension of Pyricularia oryzae 24 hr after fungicide treatments. Afterinoculation the plants were kept in a dew room at 22° C. with 100%relative humidity for 48 hr to permit spores to germinate and infect theleaf. The plants were then transferred to a greenhouse set at 24° C. fordisease to develop. Fungicide formulation, application and diseaseassessment on the sprayed leaves followed the procedures as described inthe Example A.

Example M

Evaluation of Fungicidal Activity: Tomato Early Blight (Alternariasolani; Bayer Code ALTESO):

Tomato plants (variety Outdoor girl) were propagated in soil-less Metromix, with each pot having one plant, and used when 12 to 14 days old.Test plants were inoculated with an aqueous spore suspension ofAlternaria solani 24 hr after fungicide treatments. After inoculationthe plants were kept in 100% relative humidity (one day in a dark dewchamber followed by two to three days in a lighted dew chamber at 20°C.). to permit spores to germinate and infect the leaf The plants werethen transferred to a growth room at 22° C. for disease to develop.Fungicide formulation, application and disease assessment on the sprayedleaves followed the procedures as described in the Example A.

Example N

Evaluation of Fungicidal Activity: Cucumber Anthracnose (Glomerellalagenarium; Anamorph: Colletotrichum lagenarium; Bayer Code COLLLA):

Cucumber seedlings (variety Bush Pickle) were propagated in soil-lessMetro mix, with each pot having one plant, and used in the test when 12to 14 days old. Test plants were inoculated with an aqueous sporesuspension of Colletotrichum lagenarium 24 hr after fungicidetreatments. After inoculation the plants were kept in a dew room at 22°C. with 100% relative humidity for 48 hr to permit spores to germinateand infect the leaf. The plants were then transferred to a growth roomset at 22° C. for disease to develop. Fungicide formulation, applicationand disease assessment on the sprayed leaves followed the procedures asdescribed in the Example A.

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LENGTHY TABLES The patent application contains a lengthy table section.A copy of the table is available in electronic form from the USPTO website(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20170273306A1).An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

1. A compound of Formula I:

wherein: X is C(O)R₅; Y is H, C(O)R₅, or Q; Q is

R₁ is H, alkyl, alkenyl, aryl, —C(O)R₄, each substituted with 0, 1 ormultiple R₄; R₂ is H, alkyl, alkenyl, aryl —C(O)R₄, each substitutedwith 0, 1 or multiple R₄; R₃ is H, —C(O)R₆ or —CH₂OC(O)R₆; R₄ is alkyl,alkenyl, halo, haloalkyl, alkoxy, or aryl; R₅ is alkyl, alkoxy, benzyl,benzyloxy, each substituted with 0, 1, or multiple R₇, wherein each R₇may be substituted with 0, 1, or multiple R₄; R⁶ is alkyl or alkoxy,each substituted with 0, 1, or multiple R₄; R⁷ is alkyl, alkenyl, halo,haloalkyl, alkoxy, aryl, heteroaryl, carbocyclic, heterocyclic, and—Si(R₄)₃, —C(O)R₄, —S(O)_(n)R₄, each substituted with 0, 1, or multipleR⁴; with the proviso that when R₁ and R₂ are H, X and Y are C(O)R₅ andR₅ is tert-butoxy.
 2. The compound according to claim 1 wherein X isC(O)R₅ and Y is chosen from H or C(O)R₅.
 3. The compound according toclaim 2 wherein X and Y are C(O)R₅ and R₅ is independently chosen fromalkyl, alkoxy, benzyl, or benzyloxy, each substituted with 0, 1, ormultiple R₇, wherein each R₇ may be substituted with 0, 1, or multipleR⁴.
 4. The compound according to claim 3 wherein R₁ and R₂ areindependently chosen from H, alkyl, alkenyl, aryl, or —C(O)R₄, eachsubstituted with 0, 1 or multiple R₄.
 5. The compound according to claim4 wherein R₅ is alkoxy and R₁ and R₂ are H.
 6. The compound according toclaim 5 wherein R₅ is tert-butoxy.
 7. The compound according to claim 2wherein Y is hydrogen.
 8. The compound according to claim 7 wherein R₁and R₂ are independently chosen from H, alkyl, alkenyl, aryl, or—C(O)R₄, each substituted with 0, 1 or multiple R₄.
 9. The compoundaccording to claim 8 wherein R₁ and R₂ are independently alkyl, alkenyl,aryl, or —C(O)R₄, each substituted with 0, 1 or multiple R₄.
 10. Thecompound according to claim 9 wherein R₁ and R₂ are independently alkyl,or aryl, each substituted with 0, 1 or multiple R₄.
 11. The compoundaccording to claim 8 wherein the amine is protonated to give an ammoniumsalt of a mineral acid independently chosen from hydrogen chloride,hydrogen bromide, or hydrogen iodide.
 12. The compound according toclaim 11 wherein the ammonium salt is the ammonium hydrochloride. 13.The compound according to claim 1 wherein X is C(O)R₅ and Y is Q. 14.The compound according to claim 13 wherein R₁ and R₂ are independentlychosen from H, alkyl, alkenyl, aryl, or —C(O)R₄, each substituted with0, 1, or multiple R₄.
 15. The compound according to claim 14 wherein R₁and R₂ are independently alkyl, alkenyl, aryl, or —C(O)R₄, eachsubstituted with 0, 1, or multiple R₄.
 16. A composition for the controlof a fungal pathogen including: the compound of Formula I; and aphytologically acceptable carrier material, wherein the combination ofFormula I and the carrier is useful for the control of fungal and fungallike pathogens.
 17. The composition according to claim 16, wherein thefungal or fungal like pathogen is selected from the group consisting of:Mycosphaerella graminicola, Septoria tritici, Puccinia triticinaPucciniastriiformis, Venturia inaequalis, Ustilago maydis, Uncinula necator,Rhynchosporium secalis, Magnaporthe grisea, Pseudoperonospora cubensis,Phakopsora pachyrhizi, Phaeosphaeria nodorum, Blumeria graminis tritici,Blumeria graminis hordei, Erysiphe cichoracearum, Glomerella lagenarium,Cercospora beticola, Alternaria solani, and Pyrenophora teres.
 18. Thecomposition according to claim 17, wherein the fungal pathogen or fungallike pathogen is selected from the group consisting of: Septoria triticiand Puccinia tritician)
 19. A method for the control and preventionplant disease, comprising the steps of: applying a fungicidallyeffective amount of at least one of the compounds of Formula Ito atleast one surface selected from the group consisting of: at least onesurface of a plant, an area adjacent to a plant, soil in contact with aplant, soil adjacent to a plant, seeds, and equipment for use inagriculture.
 20. The method of claim 19, wherein the fungicidallyeffective amount Formula I is applied to a surface in the range of about0.01g/m² to about 0.45 g/m² of Formula I.